WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
mam
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 6 :
A61K 31/41, 31/415, 31/53, 31/675,
C07D 235/08, 235/26, 253/06, 285/14,
C07F 9/6584
Al
(11) International Publication Number:
(43) International Publication Date:
WO 98/32439
30 July 1998 (30.07.98)
(21) International Application Number: PCT/US98/01291
(22) International Filing Date: 23 January 1998 (23.01.98)
(30) Priority Data:
60/035,991
60/042,829
23 January 1997 (23.01.97) US
8 April 1997 (08.04.97) US
(71) Applicant (for all designated States except US): SMITHKLINE
BEECHAM CORPORATION [US/US]; One Franklin Plaza,
Philadelphia, PA 19103 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): WIDDOWSON, Kather-
ine, L. [CA/US]; 1047 Old Valley Forge Road, King of
Prussia, PA 19406 (US). RUTLEDGE, Melvin, C. [US/US];
2148 Schultz Road, Lansdale, PA 19446 (US).
(74) Agents: DINNER, Dara, L. et al.; SmithKline Beecham
Corporation, Corporate Intellectual Property, UW2220, 709
Swedeland Road, P.O. Box 1539, King of Prussia, PA
19406-0939 (US).
(81) Designated States: AL, AU, BA, BB, BG, BR, CA, CN, CZ,
EE, GE, HU, ID, IL, IS, JP, KP, KR, LC, LK, LR, LT, LV,
MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL,
TR, TT, UA, US, UZ, VN, YU, ARIPO patent (GH, GM,
KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
ML, MR, NE, SN, TD, TG).
Published
With international search report.
Before the expiration of the time limit for amending the
claims and to be republished in the event of the receipt of
amendments.
(54) Title: IL-8 RECEPTOR ANTAGONISTS
(57) Abstract
This invention relates to novel compounds of Formula (I), and pharmaceutical compositions thereof, and methods of treatment of
disease states mediated by the chemokine, Interleukin-8 (IL-8).
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
AL
Albania
ES
Spain
LS
Lesotho
SI
Slovenia
AM
Armenia
FI
Finland
LT
Lithuania
SK
Slovakia
AT
Austria
FR
France
LU
Luxembourg
SN
Senegal
AU
Australia
GA
Gabon
LV
Latvia
sz
Swaziland
AZ
Azerbaijan
GB
United Kingdom
MC
Monaco
TD
Chad
BA
Bosnia and Herzegovina
GE
Georgia
MD
Republic of Moldova
TG
Togo
BB
Barbados
GH
Ghana
MG
Madagascar
TJ
Tajikistan
BE
Belgium
GN
Guinea
MK
The former Yugoslav
TM
Turkmenistan
BF
Burkina Faso
GR
Greece
Republic of Macedonia
TR
Turkey
BG
Bulgaria
HU
Hungary
ML
Mali
TT
Trinidad and Tobago
BJ
Benin
IE
Ireland
MN
Mongolia
UA
Ukraine
BR
Brazil
IL
Israel
MR
Mauritania
UG
Uganda
BY
Belarus
IS
Iceland
MW
Malawi
US
United States of America
CA
Canada
IT
Italy
MX
Mexico
uz
Uzbekistan
CF
Central African Republic
JP
Japan
NE
Niger
VN
Viet Nam
CG
Congo
KE
Kenya
NL
Netherlands
YU
Yugoslavia
CH
Switzerland
KG
Kyrgyzstan
NO
Norway
ZW
Zimbabwe
CI
Cote d'lvoire
KP
Democratic People's
NZ
New Zealand
CM
Cameroon
Republic of Korea
PL
Poland
CN
China
KR
Republic of Korea
PT
Portugal
cu
Cuba
KZ
Kazakstan
RO
Romania
cz
Czech Republic
LC
Saint Lucia
RU
Russian Federation
DE
Germany
LI
Liechtenstein
SD
Sudan
DK
Denmark
LK
Sri Lanka
SE
Sweden
EE
Estonia
LR
Liberia
SG
Singapore
WO 98/32439
PCT/US98/01291
IL-8 RECEPTOR ANTAGONISTS
5
FIELD OF THE INVENTION
This invention relates to novel benzo-2-triazole substituted compounds,
pharmaceutical compositions, processes for their preparation, and use thereof in
treating IL-8, GROcx, GRO(3, GROy and NAP-2 mediated diseases.
10
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukin-8 (IL-8), such as
neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil
chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell
15 lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils,
basophils, and a subset of T-cells. It is produced by a majority of nucleated cells
including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF,
IL-la, IL-lb or LPS, and by neutrophils themselves when exposed to LPS or
chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045
20 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144 . 2223
(1990) ; Strieter, et al., Science 243 . 1467 (1989) and J. Biol. Chem. 264 . 10621
(1989); Cassatellaet al., J. Immunol. 148 . 3216 (1992).
GROa, GROp, GROy and NAP-2 also belong to the chemokine a family.
Like IL-8 these chemokines have also been referred to by different names. For
25 instance GROa, p\ y have been referred to as MGS Aa, b and g respectively
(Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology
129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the
chemokines of the a-family which possess the ELR motif directly preceding the
CXC motif bind to the IL-8 B receptor.
30 IL-8, GROa, GROp\ GROy, NAP-2, and ENA-78 stimulate a number of
functions in vitro. They have all been shown to have chemoattractant properties for
neutrophils, while IL-8 and GROa have demonstrated T-lymphocytes, and
basophiles chemotactic activity. In addition IL-8 can induce histamine release from
basophils from both normal and atopic individuals GRO-a and IL-8 can in addition,
35 induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has
also been shown to increase the surface expression of Mac-1 (CD1 lb/CD 18) on
- 1 -
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PCT7US98/01291
neutrophils without de novo protein synthesis. This may contribute to increased
adhesion of the neutrophils to vascular endothelial cells. Many known diseases are
characterized by massive neutrophil infiltration. As IL-8, GROoc, GROp\ GROy and
NAP-2 promote the accumulation and activation of neutrophils, these chemokines
5 have been implicated in a wide range of acute and chronic inflammatory disorders
including psoriasis and rheumatoid arthritis, Baggiolini et al., FEBS Lett. 307 , 97
(1992); Miller et al., Crit. Rev. Immunol. 12 , 17 (1992); Oppenheim et al., Annu.
Rev. Immunol. 9 . 617 (1991); Seitz et al., I. Clin. Invest. 87 . 463 (1991); Miller et
al., Am. Rev. Respir. Pis. 146 . 427 (1992); Donnely et al., Lancet 341 . 643 (1993).
10 In addition the ELR chemokines (those containing the amino acids ELR motif just
prior to the CXC motif) have also been implicated in angiostasis. Strieter et al.,
Science 258, 1798 (1992).
In vitro, IL-8, GROa, GRO(3, GROy and NAP-2 induce neutrophil shape
change, chemotaxis, granule release, and respiratory burst, by binding to and
15 activating receptors of the seven-transmembrane, G-protein-linked family, in
particular by binding to IL-8 receptors, most notably the B-receptor. Thomas et al.,
I. Biol. Chem. 266 . 14839 (1991); and Holmes et al., Science 253 . 1278 (1991). The
development of non-peptide small molecule antagonists for members of this receptor
family has precedent. For a review see R. Freidinger in: Progress in Drug Research ,
20 Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor
represents a promising target for the development of novel an ti- inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been
characterized: IL-8Ra, which binds only IL-8 with high affinity, and IL-8Rb, which
has high affinity for IL-8 as well as for GROa, GRO(3, GROy and NAP-2. See
25 Holmes et al., supra; Murphy et al., Science 253 . 1280 (1991); Lee et al., J. Biol.
Chem . 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267 . 25402 (1992); and
Gayle et al., J. Biol. Chem. 268 . 7283 (1993).
There remains a need for treatment, in this field, for compounds which are
capable of binding to the IL-8 a or b receptor. Therefore, conditions associated with
30 an increase in IL-8 production (which is responsible for chemotaxis of neutrophil
and T-cells subsets into the inflammatory site) would benefit by compounds which
are inhibitors of IL-8 receptor binding.
SUMMARY OF THE INVENTION
35 This invention provides for a method of treating a chemokine mediated
disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and
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WO 98/32439
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which method comprises administering an effective amount of a compound of
Formula (I) or (II) or a pharmaceutic ally acceptable salt thereof. In particular the
chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its
5 receptors in a mammal in need thereof which comprises administering to said
mammal an effective amount of a compound of Formula (I) or (II).
The present invention also provides for the novel compounds of Formula (I),
and (II) and pharmaceutical compositions comprising a compound of Formula (I),
and (II) and a pharmaceutical carrier or diluent.
10 Compounds of Formula (I) useful in the present invention are represented by
the structure:
(Fgm
wherein
R is -NH -C(X 2 )-NH- (CRi 3 Ri 4 ) v - Z;
I \
^(CR 15 R 16 )p
15 Z is W, HET, ^ n , an optionally substituted C\_iq alkyl, an
optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
X is C(X 1 ) 2 , C(O), C(S), S(0) 2 , PO(OR 4 ), or ON-R19;
Xi is independently hydrogen, halogen, Ci-io alkyl, NR4R5, C1-10 alkyl-NR4R5,
C(0)NR4R5, optionally substituted Ci_io alkyl, Ci_io alkoxy, halosubstituted
20 Ci-io alkoxy, hydroxy, aryl, aryl C1-4 alkyl, aryloxy, aryl Ci-4 alkyloxy,
heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, or heteroaryl
Ci-4 alkyloxy;
X 2 is =0, or=S;
Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted
25 Ci-io alkyl; Ci-io alkyl; C 2 _io alkenyl; Ci-io alkoxy; halosubstituted Ci-io
alkoxy; azide; (CRgRg)q S(0) t R4, hydroxy; hydroxy Ci-4alkyl; aryl; aryl Ci_4
alkyl; aryloxy; aryl Ci_4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic,
heterocyclic Ci. 4 alkyl; heteroaryl Ci-4 alkyloxy; aryl C 2 _io alkenyl; heteroaryl
C 2 _io alkenyl; heterocyclic C 2 -io alkenyl; (CRgRg)qNR4R5 ; C 2 _io alkenyl
30 C(0)NR4R5; (CRgR8)q C(0)NR4R5; (CR 8 Rs)q C(O)NR4Rl0; S(0)3R8;
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(CR 8 R 8 )q C(0)Ri i; C2-10 alkenyl C(0)Ri l; C 2 -10 alkenyl C(0)ORi l;
C(0)R 1 1 ; (CR 8 R 8 )q C(0)OR \ 2 \ (CR 8 R 8 )q OC(O) R 1 1 ; (CR 8 R 8 )q
NR 4 C(0)Rn; (CR 8 R 8 )qC(NR 4 )NR 4 R5; (CR 8 R 8 )q NR 4 C(NR 5 )Ri i;
(CR 8 R 8 )q NHS(0)2Ri7; or (CR 8 R 8 )q S(0)2NR 4 R5; or two Ri moieties
5 together may form 0-(CH 2 ) s O or a 5 to 6 membered saturated or unsaturated
ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may
all be optionally substituted;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
10 q is 0, or an integer having a value of 1 to 10;
s is an integer having a value of 1 to 3;
t is 0, or an integer having a value of 1 or 2;
v is 0, or an integer having a value of 1 to 4;
p is an integer having a value of 1 to 3;
15 HET is an optionally substituted heteroaryl;
R4. and R5 are independently hydrogen, optionally substituted Ci- 4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci- 4 alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci_ 4 alkyl, heterocyclic, or
heterocyclic C1 _ 4 alkyl, or R4 and R5 together with the nitrogen to which they
20 are attached form a 5 to 7 member ring which may optionally comprise an
additional heteroatom selected from O/N/S;
Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted
Ci-io alkyl; Ci_io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io
alkoxy; azide; (CR 8 R 8 )q S(0)tR4; hydroxy; hydroxyCi- 4 alkyl; aryl; aryl Ci- 4
25 alkyl; aryloxy; arylCi- 4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci_ 4
alkyloxy; heterocyclic, heterocyclic Ci- 4 alkyl; aryl C2-10 alkenyl; heteroaryl
C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )q NR4.R5; C2-10 alkenyl
C(0)NR4R5; (CR 8 R 8 )q C(0)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 Ri 0 ; S(0) 3 R 8 ;
(CR 8 R 8 )q C(0)Ri 1 ; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)ORn;
30 (CR 8 R 8 )q C(0)ORi 2 ; (CR 8 R 8 )q OC(O) Ri 1; (CR 8 R 8 )q NRztC(0)Ri 1;
(CR 8 R 8 )qC(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R! i: (CR 8 R 8 )q NHS(0) 2 R a ;
or (CR 8 R 8 )q S(0>2NR 4 R5; or two Y moieties together may form 0-(CH2) s O or
a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl,
heteroaryl, and heterocyclic containing moieties may all be optionally
35 substituted;
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R.6 and R7 are independently hydrogen or a C\-4 alkyl group, or Rg and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;
5 Rs is independently hydrogen or Ci-4 alkyl;
RlO is C 1-10 alkyl C(0) 2 R8;
Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl
Ci_4alkyl, optionally substituted heteroaryl, optionally substituted
heteroarylC 1 -4alkyl, optionally substituted heterocyclic, or optionally
1 0 substituted heterocyclicC 1 _4alkyl ;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
arylalkyl;
Ri 3 and R14 are independently hydrogen, or optionally substituted Ci-4 alkyl, or
one of R13 and R14 may be optionally substituted aryl;
15 R15 and Rig are independently hydrogen, or an optionally substituted Ci-4 alkyl;
Rl7 is Ci_4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC i_4alkyl, heterocyclic, or
heterocyclicC i_4alkyl, wherein the aryl, heteroaryl and heterocyclic containing
moieties may all be optionally substituted;
Rig is hydrogen, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted
20 Ci_io alkoxy, hydroxy, arylCi_4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
Ci_4alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC 1 .4 alkyl,
wherein the aryl, heteroaryl and heterocyclic containing moieties may all be
optionally substituted;
R19 is cyano, nitro, S(0)2NR4R5, S(0)2Rn, alkyl, arylCi_4 alkyl, arylC 2-4
25 alkenyl, heteroaryl, heteroaryl-Ci_4alkyl, heteroarylC 2 -4 alkenyl, heterocyclic,
or heterocyclicC i_4 alkyl; and wherein the alkyl, aryl, heteroaryl and
heterocyclic containing moieties may all be optionally substituted;
R a is NRgR7, alkyl, arylCi .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
Ci_4alkyl, heteroarylC 2 -4 alkenyl, heterocyclic, or heterocyclicC 1 .4 alkyl; and
30 wherein the aryl, heteroaryl and heterocyclic containing moeities may all be
optionally substituted;
- 5 -
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the asterix * denoting point of attachment of the ring;
5 or a pharmaceutically acceptable salt thereof.
, Compounds of Formula (II) useful in the present invention are represented
by the structure:
10
(Ri)m
wherein
R is -NH -C(X 2 )-NH- (CR 13 R 14 ) V
(II)
I \
^ / (CR 15 R 16 )P
ZisW, HET, ^ Y ) n , optionally substituted Ci_ io alkyl, optionally
15 substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl;
Xis N, or C(Xi);
Xi is hydrogen, halogen, Ci-io alkyl, NR4R5, Ci-io alkyl-NR4R5, C(0)NR4R5,
Ci-io alkylC(0)NR4R5, optionally substituted Ci_io alkyl, Ci-io alkoxy,
halosubstituted Ci-io alkoxy, hydroxy, aryl, aryl Ci_4 alkyl, aryloxy; aryl Ci-4
20 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci_4alkyl, or
heteroaryl Ci_4 alkyloxy;
X2 is =0, or =S;
- 6 -
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Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted
Ci-io alkyl; Ci_io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci_io
alkoxy; azide; (CRgRg)q S(0) t R4, hydroxy; hydroxy Ci_4alkyl; aryl; aryl Ci-4
alkyl; aryloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic,
5 heterocyclic Ci_4alkyl; heteroaryl Ci-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl
C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CR 8 R 8 )q C(0)NR 4 R5; (CR 8 R8)q C(O)NR 4 Rl0; S(0)3Rg;
(CR 8 R 8 )q C(0)Rn; C2-10 alkenyl C(0)Rn; C 2 -10 alkenyl C(0)ORi 1;
C(0)Ri 1; (CR 8 R 8 )q C(0)ORi2; (CR 8 R 8 )q OC(O) Rl 1;
10 (CR 8 R 8 )qNR 4 C(0)Ri 1; (CR 8 R 8 )qC(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R li;
(CR 8 R 8 )q NHS(0)2Ri7; (CR 8 R 8 )q S(0)2NR 4 R5; or two Rl moieties together
may form 0-(CH2)s-0 or a 5 to 6 membered saturated or unsaturated ring; and
wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be
optionally substituted;
15 n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
q is 0, or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
20 v is 0, or an integer having a value of 1 to 4;
p is an integer having a value of 1 to 3;
HET is an optionally substituted heteroaryl;
R 4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally
substituted aryl, optionally substituted aryl Cl-4alkyl, optionally substituted
25 heteroaryl, optionally substituted heteroaryl Ci_4alkyl, heterocyclic, heterocyclic
Ci_4 alkyl, or R4 and R5 together with the nitrogen to which they are attached
form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;
Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted
30 Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io
alkoxy; azide; (CR 8 R 8 )q S(0)tR4; hydroxy; hydroxyCi- 4 alkyl; aryl; aryl Ci-4
alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci- 4
alkyloxy; heterocyclic, heterocyclic Ci_4alkyl; aryl C2-10 alkenyl; heteroaryl
C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )q NR4R5; C2-10 alkenyl
35 C(0)NR4R5; (CR 8 R 8 )q C(0)NR4R5; (CR 8 R 8 )q C(O)NR4Rl0; S(0) 3 R 8 ;
(CR 8 R 8 )q C(0)Rn; C2-10 alkenyl C(0)Rn; C 2 -10 alkenyl C(0)ORn;
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10
15
20
(CR 8 R 8 )q C(0)ORi 2 ; (CR 8 R 8 )q OC(O) Rn; (CR 8 R 8 )qC(NR4)NR 4 R5;
(CR 8 R 8 )q NR4C(NR5)R! i; (CR 8 R 8 )q NR4C(0)Ri i; (CR 8 R 8 )q NHS(0) 2 R a ;
(CR 8 R 8 )q S(0)2NR4R5; or two Y moieties together may form 0-(CH2)s-0 or a
5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl,
and heterocyclic containing moieties may all be optionally substituted;
R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;
R 8 is independently hydrogen or Ci_4 alkyl;
RlO is Ci-10 alkyl C(0)2R8;
Rll is hydrogen, Ci_ 4 alkyl, optionally substituted aryl, optionally substituted aryl
C 1 _ 4 alkyl, optionally substituted heteroaryl, optionally substituted
heteroarylCi_4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC 1 _ 4 alky 1 ;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
arylalkyl;
Rl3 and Ri 4 are independently hydrogen, or optionally substituted C1 _ 4 alkyl, or
one of R13 and R14 may be optionally substituted aryl;
R1 5 and Rig are independently hydrogen, or an optionally substituted Ci-4 alkyl;
Rl7 is Ci- 4 alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi_ 4 alkyl, heterocyclic, or
heterocyclicC i_4alkyl; and wherein the aryl, heteroaryl and heterocyclic
containing moieties may all be optionally substituted;
R a is NRgR7, alkyl, arylCi.4 alkyl, arylC2- 4 alkenyl, heteroaryl, heteroaryl-
Ci_4alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC 1 .4 alkyl; and
wherein the aryl, heteroaryl and heterocyclic containing moieties may all be
optionally substituted;
Wis
, or
the E containing ring is optionally selected from
8 -
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of the ring;
or a pharmaceutically acceptable salt thereof.
5 DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula (I) and (II) may also be used in association with
the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8
or other chemokines which bind to the IL-8 a and b receptors. Chemokine mediated
diseases for treatment, therapeutically or prophylactically, in animals include disease
10 states such as those noted herein in the Methods of Treatment section.
As readily seen, the difference between compounds of Formula (I) and (II)
lies in the unsaturation of the A containing ring, and hence the substitutions on the X
moiety. The remaining terms, defined below, are the same for both compounds of
Formula (I) and (II) unless otherwise indicated.
15
In compounds of Formula (I), suitably Ri is independently selected from
hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF3; Ci-io
alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; Ci-io alkoxy,
such as methoxy, or ethoxy; halosubstituted Ci_io alkoxy, such as
20 trifluoromethoxy; azide; (CRgRg)q S(0) t R4, wherein t is 0, 1 or 2; hydroxy;
hydroxy Ci_4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl;
aryl Cl-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C\-4 alkyloxy, such
as benzyloxy; heteroaryl; heteroaryl alkyl; heteroaryl Ci_4 alkyloxy; aryl C2-10
alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CRgRg)qNR4R5;
25 C2-10 alkenyl C(0)NR4R5; (CR 8 R 8 )q C(0)NR4R5; (CR 8 R 8 )q C(O)NR 4 Ri 0 ;
S(0)3H; S(0)3Rg; (CR 8 R 8 )q C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl
C(0)ORi 1; C(0)Ri 1; (CR 8 R 8 )q C(0)ORi 2 ; (CR 8 R 8 )q OC(O) R\ y, (CR 8 R 8 )q
NR4C(0)Rn; (CR 8 R 8 )qC(NR 4 )NR 4 R5; (CR 8 R 8 )q NR 4 C(NR 5 )Ri i; (CR 8 R 8 )q
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NHS(0)2Rn; (CRgRg)q S(0)2NR4R5; or two Ri moieties together may form
0-(CH2)s-0 or a 5 to 6 membered saturated or unsaturated ring. All of the aryl,
heteroaryl, and heterocyclic containing moieties may be optionally substituted as
defined herein below.
5
For use herein the term "the aryl, heteroaryl, and heterocyclic containing
moieties" refers to both the ring and the alkyl, or if included, the alkenyl rings, such
as aryl, arylalkyl, and aryl alkenyl rings. The term "moieties" and "rings" may be
interchangeably used throughout.
10 Suitably, s is an integer having a value of 1 to 3.
It is recognized that R^ moiety may be substituted on either the benzene ring
or the X containing ring, if possible.
When Rl forms a dioxybridge, s is preferably 1. When K\ forms an
additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene
15 ring system. These ring systems may be substituted independently, 1 to 3 times by
the other Ri moieties as defined above.
Suitably, R4 and R5 are independently hydrogen, optionally substituted Ci-4
alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally
substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or
20 heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S.
Suitably, R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6
and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring
25 which ring may optionally contain an additional heteroatom which heteroatom is
selected from oxygen, nitrogen or sulfur.
Suitably, R$ is independently hydrogen or C 1.4 alkyl.
Suitably, q is 0 or an integer having a value of 1 to 10.
Suitably, Rio is Ci_io alkyl C(0) 2 R8, such as CH2C(0)2H or
30 CH 2 C(0) 2 CH 3 .
Suitably, Rn is hydrogen, Ci-4 alkyl, aryl, aryl Ci-4 alkyl, heteroaryl,
heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Ci_4alkyl.
Suitably, R12 is hydrogen, Ci_io alkyl, optionally substituted aryl or
optionally substituted arylalkyl.
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Suitably, R13 and R14 are independently hydrogen, or an optionally
substituted Ci_4 alkyl which may be straight or branched as defined herein, or one
of R13 and R14 are an optionally substituted aryl.
Suitably, v is 0, or an integer having a value of 1 to 4.
5 When R1 3 or R14 are an optionally substituted alkyl, the alkyl moiety may
be substituted one to three times independently by halogen; halosubstituted Ci-4
alkyl such as trifluoromethyl; hydroxy; hydroxy Ci-4alkyl, C1 .4 alkoxy; such as
methoxy, or ethoxy, halosubstituted C\-\o alkoxy, S(0)tR4; aryl; NR4R5;
NHC(0)R4; C(0)NR4R5; or C(0)OR 8 .
10 Suitably, R17 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi_4alkyl,
heterocyclic, or heterocyclicCi _4alkyl, wherein all of the aryl, heteroaryl and
heterocyclic containing moieties may all be optionally substituted.
Suitably, Y is independently selected from hydrogen; halogen; nitro; cyano;
halosubstituted Ci-io alkyl; Ci_io alkyl; C2-10 alkenyl; Ci-10 alkoxy;
15 halosubstituted Ci-io alkoxy; azide; (CRgRg)q S(0)tR4; hydroxy;
hydroxyCi_4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl;
heteroarylalkyl; heteroaryl Ci_4 alkyloxy; heterocyclic, heterocyclic Ci_4alkyl; aryl
C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CRgRg)q
NR4R5; C2-10 alkenyl C(0)NR4R5; (CR 8 R 8 )q C(0)NR4R5; (CR 8 R 8 )q
20 C(O)NR4Rl0; S(0) 3 H; S(0) 3 R 8 ; (CR 8 R 8 )q C(0)Ri 1; C2-10 alkenyl C(0)Ri 1;
C2-10 alkenyl C(0)ORi 1; (CR 8 R 8 )q C(0)ORi 2 ; (CR 8 R 8 )q OC(O) R\ l;
(CR 8 R 8 )qC(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )Ri 1 ; (CR 8 R 8 )q NR4C(0)Rn;
(CRgRg)q NHS(0) 2 R a ; or (CR 8 R 8 )q S(0)2NR 4 R 5 ; or two Y moieties together
may form 0-(CH2)s-0 or a 5 to 6 membered saturated or unsaturated ring. The aryl,
25 heteroaryl and heterocyclic containing moieties noted above may all be optionally
substituted as defined herein.
When Y forms a dioxybridge, s is preferably 1 . When Y forms an additional
unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system.
These ring systems may be substituted 1 to 3 times by other Y moieties as defined
30 above.
Suitably, R a is NRgRy, alkyl, aryl Ci .4 alkyl, arylC 2-4 alkenyl, heteroaryl,
heteroaryl-Ci_4alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclicCi .4 alkyl,
wherein all of the aryl, heteroaryl and heterocyclic containing rings may all be
35 optionally substituted.
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Y is preferably a halogen, Ci-4 alkoxy, optionally substituted aryl,
optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio
Ci-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1.4 alkyl, or
hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted
5 halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or
alkyl, more preferably these groups are mono or di-substituted in the 2'- position or
2'-, 3'-position.
While Y may be substituted in any of the ring positions, n is preferably one.
While both Ri and Y can both be hydrogen, it is preferred that at least one of the
10 rings be substituted, preferably both rings are substituted.
Suitably, R is -NH -C(X 2 )-NH- (CR1 3 Ri 4 ) v - Z.
I \
^(CR 15 R 16 )p
Suitably, Z is W, HET, ( Y ) n , an optionally substituted Ci_io
alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10
15 alkynyl.
Suitably, p is an integer having a value of 1 to 3.
X2 is suitably =0, or =S.
In compounds of Formula (I), suitably X is C(Xi)2, C(O), C(S), S(0) 2 ,
PO(OR 4 ) or C=N-Ri 9.
20 Suitably, R19 is cyano, nitro, S(0) 2 NR4R5, S(0)2Rn, alkyl, arylCi_ 4 alkyl,
arylC 2-4 alkenyl, heteroaryl, heteroaryl-Ci_4alkyl, heteroarylC2_4 alkenyl,
heterocyclic, heterocyclicCi_4 alkyl, wherein the alkyl, aryl, heteroaryl and
heterocyclic containing rings may all be optionally substituted. Preferably Ri 9 is
cyano.
25
When X is C(Xi>2, X^ is suitably independently hydrogen, halogen,
NR4R5, Ci-10 alkylNR 4 R 5 , C(0)NR4R5, Ci-io alkyl-C(0)NR4R5, optionally
substituted Ci-io alkyl, Ci_io alkoxy; halosubstituted Ci_io alkoxy, aryl; aryl C1.4
alkyl; aryloxy; aryl Ci_4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic,
30 heterocyclic Ci_4alkyl; or heteroaryl Ci-4 alkyloxy. The C\_\q alkyl group may be
optionally substituted one or more times by hydroxy, NR4R5, or halogen.
Preferably, at least one of X\ is hydrogen.
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Preferably, for compounds of Formula (I), X is C(S) or a C(O) moiety, more
preferably C(O).
Suitably, Rig is hydrogen, optionally substituted Ci-io alkyl, Ci_io alkoxy,
halosubstituted Ci_io alkoxy, hydroxy, arylCj.4 alkyl, arylC 2-4 alkenyl,
5 heteroaryl, heteroaryl-Ci_4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or
heterocyclicCi_4 alkyl, wherein all of the aryl, heteroaryl and heterocyclic rings may
all be optionally substituted. Preferably R^g is hydrogen or alkyl, more preferably
hydrogen.
In compounds of Formula (II), suitably X is N, or C(Xi).
10 Preferably, when X is C(Xi ), X1 is hydrogen or halosubstituted alkyl.
It is recognized that in compounds of Formula (II) that the ring system can
exist in a tautomeric form.
15 Suitably when Z is a heteroaryl (HET) ring, it is suitably a heteroaryl ring or
ring system. If the HET moiety is a multi ring system, the ring containing the
heteroatom does not need to be directly attached to the urea moiety through the
(R1 3Ri4) v linkage, of the ring(s) in these ring systems may be optionally
substituted as defined herein. Preferably the HET moiety is a pyridyl, which may be
20 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is preferably benzimidazole,
dibenzothiophene, or an indole ring. Other rings of interest include, but are not
limited to thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline,
quinazolinyl, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
25 The HET ring may be optionally substituted independently one to five,
preferably 1 to 3 times by Y as defined above. The substitutions may be in any of
the ring(s) of the HET system, such as in a benzimidazole ring.
Suitably R15 and R1 g are independently hydrogen, or an optionally
30 substituted Ci-4 alkyl as defined above for R13 and R14.
Suitably, W is
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Suitably, the E containing ring is optionally selected from
5 The E ring denoted by its point of attachment through the asterix (*) may
optionally be present. If it is not present the ring is a phenyl moiety which is
substituted by the R\ terms as shown. The E ring may be substituted by the (Y)n
moiety in any ring, saturated or unsaturated, and is shown for purposes herein
substituted only in the unsaturated ring(s).
10
While Y in the W term may be substituted in any of the 5 ring positions of
the phenyl moiety (when E is absent), Y is preferably mono-substituted in the 2'-
position or 3'- position, with the 4'- preferably being unsubstituted. If the phenyl
ring is disubstituted, substituents are preferably in the 2' or 3' position of a
15 monocyclic ring. While both Ri and Y can both be hydrogen, it is prefered that at
least one of the rings be substituted, preferably both rings are substituted.
As used herein, "optionally substituted" unless specifically defined shall
mean such groups as halogen, such as fluorine, chlorine, bromine or iodine;
20 hydroxy; hydroxy substituted Ci-ioalkyl; Ci_io alkoxy, such as methoxy or ethoxy;
S(0) m ' Ci-io alkyl, wherein m' is 0, 1 or 2,'such as methyl thio, methyl sulfinyl or
methyl sulfonyl; amino, mono & di- substituted amino, such as in the NR4R5 group;
NHC(0)R4; C(0)NR4R5; C(0)OH; S(0)2NR4Rs; NHS(O)2R20, Ci-io alkyl, such
as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted Ci_io alkyl, such
25 CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted
arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally
substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted
heteroaryl alkyl, wherein these aryl, heteroaryl, or heterocyclic moieties may be
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substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io
alkoxy; S(O)m'Ci-i0 alkyl; amino, mono & di-substituted amino, such as in the
NR4R5 group; Ci_i 0 alkyl, or halosubstituted Ci_io alkyl, such as CF3.
R.20 is suitably Ci_4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl,
5 heteroarylCi_4alkyl, heterocyclic, or heterocyclicCi-4alkyl.
Suitable pharmaceutic ally acceptable salts are well known to those skilled in
the art and include basic salts of inorganic and organic acids, such as hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid,
10 ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid,
oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,
phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts
of compounds of Formula (I) may also be formed with a pharmaceutically
acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
15 Suitable pharmaceutically acceptable cations are well known to those skilled in the
art and include alkaline, alkaline earth, ammonium and quaternary ammonium
cations.
The following terms, as used herein, refer to:
20 • "halo" - all halogens, that is chloro, fluoro, bromo and iodo.
• "Ci_ioalkyl" or "alkyl" - both straight and branched chain radicals of 1 to
10 carbon atoms, unless the chain length is otherwise limited, including, but not
limited to, methyl, ethyl, n-propyl, r'so-propyl, n-butyl, .sec-butyl, wo-butyl, tert-
butyl, n-pentyl and the like.
25 • The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of
3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl,
and the like.
• The term "alkenyl" is used herein at all occurrences to mean straight or
branched chain radical of 2-10 carbon atoms, unless the chain length is limited
30 thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-mefhyl-l-
propenyl, 1-butenyl, 2-butenyl and the like.
• "aryl" - phenyl and naphthyl;
• "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or
"heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more
35 rings contain one or more heteroatoms selected from the group consisting of N, O or
S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline,
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isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole,
triazole, imidazole, or benzimidazole.
• "heterocyclic" (on its own or in any combination, such as
"heterocyclicalkyl") - a saturated or partially unsaturated 4-10 membered ring
5 system in which one or more rings contain one or more heteroatoms selected from
the group consisting of N, O, or S; such as, but not limited to, pyrrolidine,
piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
• The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used
herein to mean Ci_io alkyl, as defined above, attached to an aryl, heteroaryl or
10 heterocyclic moiety, as also defined herein, unless otherwise indicated.
• "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio"
refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(0)2
moiety.
• The term "wherein two Ri moieties (or two Y moieties) may together form
15 a 5 or 6 membered saturated or unsaturated ring" is used herein to mean the
formation of an aromatic ring system, such as napthylene, or is a phenyl moiety
having attached a 6 membered partially saturated or unsaturated ring such as a C(,
cycloalkenyl, i.e. hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
20 Exemplified compounds of Formula (I) include:
N-4-(Benzimidazoline-2-one-N'-(2'-bromophenyl)urea;
N-4-( lH,3H-2, 1 ,3-benzothiazole 2,2-dioxide)-N'-(2-bromophenyl) urea
N-4-(7-Cyano- 1 -N-methyl-benzimidazoline-2-thione)-N'-(2,3-dichlorophenyl) urea
N-4-(7-Cyano-benzimidazoline-2-thione)-N'-(2 bromophenyl) urea
25 N-4-(7-Cyano-l-methyl-benzimidazoline-2-thione)-N'-(2 bromophenyl) urea
N-4-(7-Cyano- 1 -methylbenzimidazoline-2-one)-N'-(2,3-dichlorophenyl) urea
N-4-(7-Cyano-benzimidazoline-2-one)-N'-(2-bromophenyl)urea
N-4-(7-Cyano-benzimidazoline-2-thione)-N'-(2,3-dichlorophenyl) urea
N-4-(7-Cyano benzimidazoline-2-imine)-N'-(2-bromophenyl) urea
30 N-(4-Cyano-2-oxo-3-methylbenzimidazol-7-yl)-N'-(2-bromophenyl) urea
Exemplified compounds of Formula (II) include:
N-7-(Benzotriazole)-N'-(2-bromophenyl)urea;
N-7-(4-Bromobenzotriazole)-N'-(2,3-dichorophenyl)urea;
35 N-7-(4-Bromo-2-trifluoromethyl-benzimidazolyl)-N'-(2-bromophenyl)urea;
N-4-(2-Trifluoromethyl-benzimidazolyl)-N'-(2-bromophenyl)urea
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N-7-(4-Cyano-benzotriazole)-N'-(2,3-dichlorophenyl) urea
N-(2-Bromophenyl)-N'-7-(4-cyano-benzotriazole) urea
N-7-(4-Cyano-2-trifluoromethyl-benzimidazolyl)-N'-(2-bromophenyl) urea
N-7-(4-Cyano-benzimidazolyl)-N'-(2,3-dichlorophenyl) urea
5 N-7-(4-Cyano-benzimidazolyl)-N'-(2-bromophenyl) urea
N-7-(4-Cyano-benzotriazole)-N'-(2,3-dichorophenyl)urea
For purposes herein, the above noted nomenclature is based upon the numbering of
the ring systems as follows:
10 (for Formula (I)); and ' (for Formula (II)).
Methods of Preparation
The compounds of Formula (I) may be obtained by applying synthetic
procedures, some of which are illustrated in the Schemes below. The synthesis
provided for in these Schemes is applicable for the producing of Formula (I) having
15 a variety of different Z and Ri groups which are reacted, employing optional
substituents which are suitably protected to achieve compatibility with the reactions
outlined herein. Subsequent deprotection, in those cases, then affords compounds of
the nature generally disclosed. Once the urea nucleus has been established, further
compounds of these formulas may be prepared by applying standard techniques for
20 functional group interconversion, well known in the art. While the schemes are
shown with various compounds of Formula (I) this is merely for illustration
purposes only and not a limitation on the extent of synthesis available using these
methods.
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Scheme 1
+ .o
N
a)NaN0 2 , HOAc
If the 2-nitro substituted heterocyclic compound 2-scheme 1 is not
5 commercially available it can be made by treating the commercially available 3-nitro
phenylene diamine 1 -scheme 1 with sodium nitrite in a protic solvent such as HOAc.
Scheme 2
+ .o
a)Triphosgene, Et3lM, DMF
If the 2-nitro substituted heterocyclic compound 2-scheme 2 is not
commercially available it can be made by treating the commercially available 3-nitro
phenylene diamine 1 -scheme 2 with triphosgene and triethylamine in DMF or the
thiophosgene to form the thio urea.
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Scheme 3
+ ,o
- N
a)Trifluoroacetic anhydride b)Toluene, reflux
If the 2-nitro substituted heterocyclic compound 2-scheme 3 is not
5 commercially available it can be made by treating the commercially available 3-nitro
phenylene diamine 1 -scheme 3 with the corresponding anhydride then refluxing in
toluene.
Scheme 4
a) Et 3 N, THF, -70°C b) SOCI 2 c) m-CPBA d) H 2 , Pd/C e) NaN0 3> 3M H 2 S0 4
If the 2-nitro substituted heterocyclic compound 3-scheme 4 is not
commercially available it can be made by treating compound 2-scheme 4 . under
standard nitrating conditions (using HNO3 or NaNC>3) at 23°C. If heterocyclic
15 compound 2-scheme 4 is not commercially available it can be made from the
commercially available 1, 2-dibenzyldiamine 1 -scheme 4 with triethylamine at
-70°C, then thionyl chloride followed by oxidation with m-CPBA and reduction of
the benzyl groups using H2/ Pd in MeOH.
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Scheme 5
a) PhOP(0)CI 2 b) NaNQ 3
If the 2-nitro substituted heterocyclic compound 2- scheme 5 is not
commercially available it can be made by treating the commercially available 1, 2-
diamine 1 -scheme 5 with PhOP(0)Cl2 followed by standard nitrating conditions
(using HNO3 or NaN0 3 ) at 23°C.
Scheme 6
10
a) Formaldehyde, reflux
If the heterocyclic compound 2-scheme 6 is not commercially available it can
be made by treating the commercially available 1, 2-diamine 1 -scheme 6 with
formaldehyde at reflux.
Scheme 7
NHL
a) H 2 Pd/C, MeOH b) PhNCO, DMF, 80°C
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If the desired aniline 2-scheme 7 is not commercially available the
corresponding nitro compound 1 -scheme 4 is then reduced under standard condition
(H2 Pd/C or SnCl2)- The ortho substituted phenyl urea in 3 -scheme 7 may be
prepared by standard conditions involving the condensation of the commercially
5 available substituted aryl isocyanate(Aldrich Chemical Co., Milwaukee,Wi.) with
the corresponding aniline 2-scheme 7 in an aprotic solvent such as (DMF or
toluene).
Scheme 8
a) CuCN,pyridine,DMF b)TMHI,DMSO,Na-tertpentoxide c)NaNO z , HOAc d)Pd/C H 2 MeOH
If the 7-amino substituted heterocyclic compound 4-scheme 8 is not
commercially available it can be made by treating the commercially available 2-
bromo-5-nitroaniline 1 -scheme 8 with copper (I) cyanide and pyridine in an aprotic
15 solvent such as DMF to form the 2-cyano-5-nitroaniline 2-scheme 8 . The diamine
3-scheme 8 can be formed by reacting 2-cyano-5-nitroaniline 2-scheme 8 with
tetramethyl hydrazine iodide and a strong hindered base such as sodium t-pentoxide,
in an aprotic solvent such as DMSO. The 7-amino-4-cyanobenzotriazole 4-scheme
8 can be made by reacting the diamine 3-scheme 8 with sodium nitrite, in a protic
20 solvent such as HOAc, followed by reduction of the nitro group with a suitably
reducing agent, such as Pd/C in MeOH.
The amino substituted heterocyclic compound 4-scheme-8 can then be
converted to the corresponding urea by condensation with a commercially available
isocyanate.
25
SYNTHETIC EXAMPLES
The invention will now be described by reference to the following examples which
are merely illustrative and are not to be construed as a limitation of the scope of the present
invention. All temperatures are given in degrees centigrade, all solvents are highest
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available purity and all reactions run under anhydrous conditions in an argon atmosphere
unless otherwise indicated.
In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were
performed upon a VG Zab mass spectrometer using fast atom bombardment, unless
5 otherwise indicated. ^H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz
using a Bruker AM 250 or Am 400 spectrometer. Multiplicities indicated are: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a
saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to
the principal reactant.
10 General Method B: Synthesis of N, N'- phenyl urea To a solution of
phenyl isocyanate(1.0 equiv.) in dimethyl formamide (1ml) the corresponding
aniline (1.0 equiv.) was added. The reaction mixture was stirred at 80°C until
complete (3-16 hours), then removed solvent under vacuum. The purification, yields
and spectral characteristics for each individual compound are listed below.
15
Example 1
Preparation of N-[5-Bromo-2-benzotriazolel-N'-r2, 3-dichlorophenvll urea
a) Preparation of 4-nitrobenzotriazole
To a solution of 3-nitro-phenylenediamine(15.3g, 100 millimole (hereinafter
20 mmol)) in acetic acid (50milliliter (hereinafter"ml")) was stirred with sodium
nitrite(6.9g, 100 mmol). The mixture was then heated to 60° C for 1 hour
(hereinafter "hr"). The reaction was then cooled to room temperature and water was
added, the desired product precipitated out of solution and the mixture was filtered
to give the desired product(10.7 grams (hereinafter"g"), 65 %). 'H NMR
25 (CD3SOCD3): 6 8.58 (d, 1H), 8.44 (d, 1H), 7.61 (t, 1H).
b) Preparation of 4-aminobenzotriazole
To a solution of 4-nitrobenzotriazole(4g, 24.4mmol) in methanol(250ml) was
added 10% Pd/C (l.Og). The mixture was flushed with argon, then hydrogen was
bubbled through the solution for 10 minutes (hereinafter "min") and a hydrogen
30 atmosphere was maintained at balloon pressure for 4 hors. The reaction mixture was
flushed with argon and 10% Pd/C (l.Og) was additionally added and a hydrogen
atmosphere was maintained at balloon pressure overnight. The mixture was filtered
through celite and the celite was washed with methanol. The solvent was evaporated
and chromatography of the resulting solid on silica gel (5%MeOH/ CH,C1 2 ) gave the
35 desired product(2.0g, 82 %). 'H NMR (CD 3 S0 2 CD 3 ): 5 8.71 (s, 1H), 7.16 (t, 1H),
6.75 (d, 1H), 6.36 (d, 1H), 5.90 (s, 1H).
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c) Preparation of 4-amino-7-bromobenzotriazole
To a solution of 4-aminobenzotriazole(550 milligram (hereinafter "mg"),
4. lmmol) in acetic acid (10ml) was added potassium bromide (520mg, 4.4mmol),
ammonium molybdate(67mg, 0.55mmol) and hydrogen peroxide (0.5ml, 30%). The
5 mixture was stirred at 25° C for 3 hors. The solvent was evaporated and
chromatography of the resulting solid on silica gel (EtOAc/
Hexane(lequiv./lequiv.)) gave the desired product(400 mg, 45 %). 'H NMR
(CD 3 S0 2 CD 3 ): 5 7.29 (d, 1H), 6.49 (d, 1H), 6.05 (bs, 3H).
d) Preparation of N-7-[4-Bromo-[2,4]-benzotriazole]-N'-[2, 3-dichlorophenyl] urea
10 N-[5-Bromo-2-benzotriazole]-N'-[2, 3-dichlorophenyl] urea was prepared
from 4-amino-7-br0mobenzotriazole (330mg, 1.50 mmol) according to the
procedure in General Method B. The product was purified by chromatography of
the resulting solid on silica gel(EtOAc/ hexane(2equiv./3equiv.)). (410mg, 68%).
'H NMR (CD3SOCD3): 5 10.42 (s, 1H), 9.25 (s, 1H), 8.20 (dd, 1H), 7.96 (d, 1H),
15 7.64 (d, 1H), 7.33 (m, 2H).
Example 2
Preparation of N-7-rbenzimidazolin-3-onel-N'-r2-bromophenyll urea
a) Preparation of 4-nitro-benzimidazolin-2-one
20 To a solution of 3-nitro-phenylenediamine( 1 .0g, 6.53 mmol) in
dimethylforamide(20ml) was added triphosgene(0.775g, 2.60 mmol)and
triethylamine(lml, 7.80mmol). The mixture was then heated to 80° C for aboutl hour.
The solvents were then evaporated and the product was precipitated out of solution with
methylene chloride/hexane(lequiv./20equiv.). (700mg, 64%). 'H NMR (CD3SO2CD3):
25 5 11.61 (s, 1H), 11.35 (s, 1H), 7.85 (d, 1H), 7.34 (d,lH),7.15 (t, 1H).
b) Preparation of 4-amino-benzimidazolin-2-one
To a solution of 4-nitro-benzimidazolin-2-one (700mg, 3.9mmol) in
methanol(50ml)and acetic acid(lOml) was added 10% Pd/C (200mg). The mixture
was flushed with argon, then hydrogen was bubbled through the solution for 10 min.
30 and a hydrogen atmosphere was maintained at balloon pressure overnight. The
mixture was filtered through celite and the celite was washed with methanol. The
solvent was evaporated and chromatography of the resulting solid on silica gel
(10%MeOH/ CH 2 C1 2 ) gave the desired product(500mg, 86 %). 'H NMR
(CD 3 S0 2 CD 3 ): 6 10.34 (s, 1H), 10.01 (s, 1H), 6.66 (t, 1H), 6.24 (d,lH), 6.22 (d,
35 1H), 5.15 (bs, 2H).
c) Preparation of N-[benzimidazolin-3-one]-N'-[2-bromophenyl] urea
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N-[benzimidazolin-3-one]-N'-[2-bromophenyl] urea was prepared from 4-
amino-benzimidazolin-2-one (80mg, 0.54 mmol) according to the procedure in
General Method B. The product was purified by chromatography of the resulting
solid on silica gel(EtOAc/ hexane(lequiv./lequiv.)). (120mg, 64%). 'H NMR
5 (CD3SOCD3): 5 10.68 (s, 1H), 10.03 (s, 1H), 9.08 (s, 1H), 8.15 (d, 1H), 8.08 (s,
1H), 7.62 (d, 1H), 7.34 (t, 1H), 6.99 (t, 1H), 6.92 (d, 2H), 6.73 (d, 1H).
Example 3
Preparation of N-r4-bromo-2-trifluoromethyl-7-benzimidazolyll-N'-r2-
10 bromophenyll urea
a) Preparation of 4-nitro-2-trifluoromethylbenzimidazole
To a solution of 3-nitro-phenylenediamine(1.0g, 6.53 mmol) was added
trifluoroacetic anhydride(1.37g, 6.53mmol). The mixture was then stirred for 1 hr. The
solvents were then evaporated and the product was refluxed in toluene for 2 hrs. The
15 solvents were then evaporated and the desired product was obtained(1.43g, 95%). 'H
NMR (CD3SO2CD3): 5 9.40 (s, 1H), 8.31 (d, 1H), 8.39 (d, 1H), 7.58 (t, 1H).
b) Preparation of 4-amino-2-trifluoromethylbenzimidazole
To a solution of 4-nitro-2-trifluoromethylbenzimidazole (700mg, 3.0mmol)
in methanol (5 0ml) and was added 10% Pd/C (200mg). The mixture was flushed
20 with argon, then hydrogen was bubbled through the solution for 10 min. and a
hydrogen atmosphere was maintained at balloon pressure overnight. The mixture
was filtered through celite and the celite was washed with methanol. The solvent
was evaporated and chromatography of the resulting solid on silica gel (10%MeOH/
CH 2 C1 2 ) gave the desired product(560mg, 93 %). 'H NMR (CD3SO2CD3): 5 10.49
25 (s, 1H), 7.09 (t, 1H), 6.72 (d, 1H), 6.30 (d, 1H), 5.52 (bs, 2H).
c) Preparation of 4-amino-7-bromo-2-trifluoromethylbenzimidazole
To a solution of 4-amino-2-trifluoromethylbenzimidazole (180mg, 0.9mmol)
in acetic acid(lOml) was added potassium bromide(l 17mg, 0.99mmol), ammonium
molybdate(12mg, 0.099mmol) and hydrogen peroxide(0.2ml,30%). The mixture
30 was stirred at 25° C for 3 hrs. The solvent was evaporated and chromatography of
the resulting solid on silica gel (EtOAc/ Hexane(lequiv./lequiv)) gave the desired
product(103mg, 39 %). 'H NMR (CD 3 OD): 8 7.1 1 (d, 1H), 6.35 (d, 1H).
d) Preparation of N-[4-bromo-2-trifluoromethyl-7-benzimidazolyl]-N'-[2-
bromophenyl] urea
35 N-[4-bromo-2-trifluoromethyl-7-benzimidazolyl]-N'-[2-bromophenyl] urea
was prepared from 4-amino-7-bromo-2-trifluoromethylbenzimidazole (33mg, 0.54
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mmol) according to the procedure in General Method B. The product was purified
by chromatography of the resulting solid on silica gel(EtOAc/ hexane
(lequiv./lequiv.)). (35mg, 63%). 'H NMR (CD3SOCD3): 5 9.95 (s, 1H), 9.54 (s,
1H), 9.07 (s, 1H), 8.06 (d, 1H), 7.99 (d, 1H), 7.62 (d, 1H), 7.33 (t, 1H), 7.01 (t, 1H).
5
Example 4
Preparation of N-r4-Triazolophenyll-N'-r2-bromophenyll urea
a) Preparation of 2, 6-Dinitro( 1 -phenylsulfonyl)aniline
To the solution of 2, 6-dinitroaniline (2 g, 10.92 mmol) in THF (20 mL),
10 sodium hydride (437 mg, 10.92 mmol) was added. After 10 minutes,
benzenesulfonyl chloride (1.4 mL, 10.92 mmol) was added. The reaction mixture
was stirred at room temperature for 16 hours. Then, the reaction mixture was
partitioned between ethyl acetate and water. The combined organic layer was dried
over MgS0 4 , filtered and concentrated under reduced pressure and chromatography
15 of the resulting liquid on silica gel (hexane/ethyl acetate(5equiv/.lequiv.)) gave
product (2.6 g, 74%). EI-MS m/z 324 (M + ).
b) Preparation of 2, 6-Diamino(l-phenylsulfonyl)aniline
To the solution of 2, 6-Dinitro(l-phenylsulfonyl)aniline (450 mg, 1.39 mmol) in
ethanol (10 mL), Tin (II) chloride (1.57 g, 6.95 mmol) was added. The reaction mixture
20 was stirred at reflux for 4 hours. Then was cooled to room temperature. The NaHCC>3
(aqueous) was added to pH= 7. Then was extracted with ethyl acetate (3x). The
combined organic layer was dried over MgS0 4 , filtered and concentrated under reduced
pressure to give product (338mg, 92%). EI-MS m/z 264 (M + ).
c) Preparation of N-(2-Benzenesulfonylamino-3-aminophenyl)-N'-(2-
25 bromophenyl)urea
To a solution of 2-bromo phenyl isocyanate (0.16 mg, 1.28 mmol) in DMF
(1.5 mL), the 2, 6-diamino(l-phenylsulfonyl)aniline (338 mg, 1.28 mmol) was
added. The reaction mixture was stirred at 80.°C for 16 hours, then cooled to room
temperature. Chromatography of the resulting liquid on silica gel (hexane/ethyl
30 acetate(5equiv./lequiv. to lequiv./lequiv.)) gave product (430 mg, 73%). EI-MS
m/z461(M + ).
d) Preparation of N-(4-Triazolophenyl)-N'-(2-bromophenyl)urea)
The N-(2-Benzenesulfonylamino-3-aminophenyl)-N'-(2-bromophenyl)urea
(235 mg, 0.51 mmol) was added to HC1/H 2 0 (0.51 mL/1.02 mL), cooled to 0"C.
35 Sodium nitrate (35.4 mg, 0.5 1 mmol) was added to the reaction mixture. The
reaction mixture was stirred at 0"C for 30 minutes. The sodium cyanide (25 mg,
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0.5 1 mmol) was added to reaction mixture and warmed to room temperature. The
reaction mixture was stirred at room temperature for 18 hours. Then it was extracted
with three times by ethyl acetate. The organic extracts were combined, dried over
MgS0 4 , filtered and concentrated under reduced pressure and chromatography of the
5 resulting solid on silica gel gave product (100 mg, 59%). EI-MS m/z 333 (M + ).
Example 5
Preparation of N-7-[2-trifluoromethylbenzimidazolyll-N'-r2-bromophenyll urea
a) Preparation of 4-nitro-2-trifluoromethylbenzimidazole
10 To a solution of 3-nitro-phenylenediamine(1.0g, 6.53 mmol) was added
trifluoroacetic anhydride(1.37g, 6.53mmol). The mixture was then stirred for 1 hr.
The solvents were then evaporated and the product was refluxed in toluene for 2 hrs.
The solvents were then evaporated and the desired product was obtained (1.43g,
95%). 'H NMR (CD3SO2CD3): 5 9.40 (s, 1H), 8.31 (d, 1H), 8.39 (d, 1H), 7.58 (t,
15 1H).
b) Preparation of 4-amino-2-trifluoromethylbenzimidazole
To a solution of 4-nitro-2-trifluoromethylbenzimidazole (700mg, 3.0mmol)
in methanol(50ml)and was added 10% Pd/C (200mg). The mixture was flushed
with argon, then hydrogen was bubbled through the solution for 10 min. and a
20 hydrogen atmosphere was maintained at balloon pressure overnight. The mixture
was filtered through celite and the celite was washed with methanol. The solvent
was evaporated and chromatography of the resulting solid on silica gel (10%MeOH/
CH 2 C1 2 ) gave the desired product(560mg, 93 %). ] H NMR (CD3SO2CD3): 5 10.49
(s, 1H), 7.09 (t, 1H), 6.72 (d, 1H), 6.30 (d,lH), 5.52 (bs, 2H).
25 c) Preparation of N-7-[2-trifluoromethyl benzimidazolyl]-N'-[2-bromophenyl] urea
N-7-[2-trifluoromethyl benzimidazolyl]-N'-[2-bromophenyl] urea was
prepared from 4-amino-2-trifluoromethylbenzimidazole (360mg, 1.79 mmol)
according to the procedure in General Method B . The product was purified by
chromatography of the resulting solid on silica gel(EtOAc/
30 hexane(lequiv./lequiv.)). (35mg, 63%). 'H NMR (CD3SO2CD3): 5 9.94 (s, 1H),
9.89 (s, 1H), 9.02 (s, 1H), 8.09 (d, 1H), 8.00 (d, 1H), 7.61 (d, 1H), 7.32 (m, 2H),
7.20 (d, 1H), 7.00 (t, 1H).
Example 6
35 Preparation of N-(4-Cyano- lH-benzotriazol-7-yl)-N'-(2,3-dichlorophenyl) urea
a) Preparation of 2-cyano-5-nitroaniline
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To a solution of 2-bromo-5-nitroaniline (5.0g, 23 mmol) in dimethylforamide
(100ml) and pyridine (20ml) was stirred with copper(I) cyanide (2.05g,64 mmol).
The mixture was then heated to 160° C for 48 hrs. The reaction was then cooled to
room temperature and filtered through celite, the celite was washed with ethyl
5 acetate. The solvent was evaporated and chromatography of the resulting solid on
silica gel (25%EtOAc/ Hexane) gave the desired product (2.64 g, 70 %). 'H NMR
(CD3COCD3): 8 7.75 (s, 1H), 7.70 (d, 1H), 7.44 (dd, 1H), 6.25(bs, 2H).
b) Preparation of 2-cyano-5-nitro-phenylenediamine
To a solution of 2-cyano-5-nitroaniline (435 mg, 2.67mmol) in
10 dimethylsulfoxide (25ml) was added tetramethylhydrazine iodide (534 mg,
2.67mmol) and sodium t-pentoxide (880 mg, 8.01mmol). The mixture was stirred at
room temperature for 12 hrs., the reaction was quenched with 10% HC1.
Precipitated solids were filtered and the remaining solution was extracted with ethyl
acetate, the solvent was evaporated and chromatography of the resulting solid on
15 silica gel (25%EtOAc/ Hexane) gave the desired product (254 mg, 53 %). 'H NMR
(CD3COCD3): 8 7.49 (d, 1H), 7.03 (bs, 2H), 6.80 (d, 1H), 5.78(bs, 2H).
c) Preparation of 4-cyano-7-nitrobenzotriazole
To a solution of 2-cyano-5-nitro-phenylenediamine (120 mg, 0.67 mmol) in
acetic acid (20ml) was stirred with sodium nitrite (50 mg, 0.72 mmol). The mixture
20 was then heated to 60° C for 1 hr. The reaction was then cooled to room
temperature and the solvents were evaporated and chromatography of the resulting
solid on silica gel (50%EtOAc/ Hexane) gave the desired product (120 mg, 95 %).
'H NMR (CD3COCD3): 8 8.70 (d, 1H), 8.25 (d, 1H).
d) Preparation of 4-cyano-7-aminobenzotriazole
25 To a solution of 4-cyano-7-nitrobenzotriazole (120 mg, 0.63mmol) in
methanol (250ml) was added 10% Pd/C (l.Og). The mixture was flushed with
argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen
atmosphere was maintained at balloon pressure for 4 hrs. The reaction mixture was
flushed with argon and 10% Pd/C (l.Og) was additionally added and a hydrogen
30 atmosphere was maintained at balloon pressure for 1 hr. The mixture was filtered
through celite and the celite was washed with methanol. The solvent was evaporated
and chromatography of the resulting solid on silica gel (5%MeOH/ CH 2 C1 2 ) gave the
desired product (95 mg, 94 %). 'H NMR (CD3OD): S 7.58 (d, 1H), 6.53 (d, 1H).
e) Preparation of N-[5-cyano-2-benzotriazole]-N'-[2,3-dichlorophenyl] urea
35 N-[5-cyano-2-benzotriazole]-N'-[2,3-dichlorophenyl] urea was prepared from
7-amino-4-cyanobenzotriazole (95mg, 0.60 mmol) according to the procedure in
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General Method B. The product was purified by chromatography of the resulting
solid on silica gel (EtOAc/ hexane(2equiv./3equiv.)). (410mg, 68%). 'H NMR
(CD3COCD3): 8 10.85 (s, 1H), 9.40 (s, 1H), 8.34 (d, 1H), 8.20 (d, 1H), 7.94 (d,
1H),7.36 (d, 1H), 7.31 (t, 1H).
5
Example 7
Preparation of N-(2-Bromophenyl)-N'-(4-cyano- 1 H-benzotriazol-7-yl) urea
To a solution of 2-bromo-5-nitroaniline (5.0g, 23 mmol) in dimethylforamide
(100ml) and pyridine (20ml) was stirred with copper(I) cyanide (2.05g,64 mmol).
10 The mixture was then heated to 160° C for 48 hrs. The reaction was then cooled to
room temperature and filtered through celite, the celite was washed with ethyl
acetate. The solvent was evaporated and chromatography of the resulting solid on
silica gel (25%EtOAc/ Hexane) gave the desired product(2.64 g, 70 %). 'H NMR
(CD3COCD3): 5 7.75 (s, 1H), 7.70 (d, 1H), 7.44 (dd, 1H), 6.25(bs, 2H).
15 b) Preparation of 2-cyano-5-nitro-phenylenediamine
To a solution of 2-cyano-5-nitroaniline (435 mg, 2.67mmol) in
dimethylsulfoxide (25ml) was added tetramethylhydrazine iodide(534 mg,
2.67mmol) and sodium t-pentoxide (880 mg, 8.01mmol). The mixture was stirred at
room temperature for 12 hrs., the reaction was quenched with 10% HC1.
20 Precipitated solids were filtered and the remaining solution was extracted with ethyl
acetate, the solvent was evaporated and chromatography of the resulting solid on
silica gel(25%EtOAc/ Hexane) gave the desired product (254 mg, 53 %). 'H NMR
(CD3COCD3): 8 7.49 (d, 1H), 7.03 (bs, 2H), 6.80 (d, 1H), 5.78(bs, 2H).
c) Preparation of 4-cyano-7-nitrobenzotriazole
25 To a solution of 2-cyano-5-nitro-phenylenediamine (120 mg, 0.67 mmol) in
acetic acid (20ml) was stirred with sodium nitrite (50 mg, 0.72 mmol). The mixture
was then heated to 60° C for 1 hr. The reaction was then cooled to room
temperature and the solvents were evaporated and chromatography of the resulting
solid on silica gel (50%EtOAc/ Hexane) gave the desired product (120 mg, 95 %).
30 'H NMR (CD3COCD3): 8 8.70 (d, 1H), 8.25 (d, 1H).
d) Preparation of 4-cyano-7-aminobenzotriazole
To a solution of 4-cyano-7-nitrobenzotriazole (120 mg, 0.63mmol) in
methanol (250ml) was added 10% Pd/C (l.Og). The mixture was flushed with
argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen
35 atmosphere was maintained at balloon pressure for 4 hrs. The reaction mixture was
flushed with argon and 10% Pd/C (l.Og) was additionally added and a hydrogen
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atmosphere was maintained at balloon pressure for 1 hr. The mixture was filtered
through celite and the celite was washed with methanol. The solvent was evaporated
and chromatography of the resulting solid on silica gel (5%MeOH/ CH 2 C1 2 ) gave the
desired product (95 mg, 94 %). 'H NMR (CD 3 OD): 8 7.58 (d, 1H), 6.53 (d, 1H).
5 e) Preparation of N-[4-cyano-[l,4]-benzotriazol-7yl]-N'-[2-bromophenyl] urea
N-[5-cyano-2-benzotriazole]-N'-[2-bromophenyl] urea was prepared from 7-
amino-4-cyanobenzotriazole (95mg, 0.60 mmol) according to the procedure in
General Method B. The product was purified by chromatography of the resulting
solid on silica gel(EtOAc/ hexane(2equiv./3equiv.)). (410mg, 68%). ] H NMR
10 (CD3S0 2 CD3): 6 10.83 (s, 1H), 9.18 (s, 1H), 8.20 (d, 1H), 8.05 (d, 1H), 7.99 (d,
1H), 7.66 (d, 1H), 7.40 (t, 1H), 7.06 (t, 1H).
15
20
Using the analogous procedures to those indicated above or in the schematics, the
following compounds may be synthesized:
Example 8 : N-(2H,4H-3,2,4-benzothiazole 3,3-dioxide)-N'-(2-bromophenyl) urea
iH NMR (DMSO-J 6 ) 5 10.96(s, 1H), 10.32(s, 1H), 9.05(s, 1H), 8.49(s, 1H), 8.08(d,
1H, J=11.50Hz), 7.63(d, 1H, J=l 1.50Hz), 7.35(t, 1H), 7.18(d, 1H, J=l 1.50), 7.01(t,
lH),6.91(t, 1H), 6.60(d, 1H, J=11.50)
Example 9 : N-(5-cyano-4-N-methyl-benzimidazolin-3-thione)-N'-(2,3-dichloro-phenyl)
urea *H NMR (DMSO-d 6 ) 8 1 1.20(s, 1H), 9.52(s, 1H), 8.62(s, 1H), 8.15(m,2H),
7.61(d, 1H, J=13.25Hz), 7.45(d, 1H, J=13.25Hz), 7.37(m, 2H), 3.94(d, 3H)
25 Example 10 : N-(5-cyano-benzimidazolin-3-thione)-N'-(2 bromophenyl) urea
NMR (DMSCM 6 ) 8 11.57(s, 1H), 10.43(s, 1H), 9.51(s, 1H), 8.31(s, 1H), 8.09(d,
1H, J=13.25Hz), 7.68(d, 1H, J=13.25Hz), 7.54(d, 1H, J=13.25), 7.44-7.36(m, 2H),
7.07(t, 1H)
30 Example 1 1 : N-(5-cyano-4-N-methyl-benzimidazolin-3-thione)-N'-(2 bromophenyl)
urea iHNMR (DMSO-^ 6 ) 8 11.25(s, 1H), 9.51(s, 1H), 8.31(s, 1H), 8.09(d, 1H,
J=13.25), 7.67(d, 1H, J=13.25Hz), 7.61(d, 1H, J=13.25Hz), 7.50(d, 1H, J=13.25),
7.39(t, 1H), 7.06(t, 1H), 3.94(s, 3H)
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Example 12 : N-(4-Cyano-2-oxo-3-methylbenzimidazol-7-yl)-N'-(2,3-
dichlorophenyl) urea l H NMR (DMSO-</ 6 ) 8 10.94(s, 1H), 9.46(s, 1H), 8.65(s, 1H),
8.18(m, 1H), 7.40-7.31(m, 3H), 7.26(d, 1H, J=13.25Hz), 3.55(s, 3H)
5 Example 13 : N-(4-Cyano-2-oxo-2,3-dihydrobenzimidazol-7-yl)-N'-(2-bromo-
phenyl)urea l U NMR (DMSO-d 6 ) 8 11.86(s, 1H), 10.82(s, 1H), 9.94(s, 1H), 8.70(s,
1H), 8.65(d, 1H, J=13.25Hz), 8.11(d, 1H, J=13.25Hz), 7.85(t, 1H), 7.76(m, 2H),
7.50(t, 1H)
1 0 Example 14 : N-(4-Cyano-2-trifluoromethyl-7-benzimidazolyl)-N'-(2-bromophenyl)
urea l H NMR (DMSO-d 6 ) 8 10.30(s, 1H), 9.25(s, 1H), 8.24(s, 1H), 7.96(m, 2H),
7.85(d, 1H, J=13.25Hz), 7.66(d, 1H, J=13.25Hz), 7.49(t, 1H), 7.07(t, 1H)
Example 15 : N-(4-Cyano-7-benzimidazolyl)-N'-(2,3-dichlorophenyl) urea iHNMR
15 (DMSO-^ 6 ) 8 10.45(s, 1H), 10.34(s, 1H), 9.48(s, 1H), 8.44(s, 1H), 8.15(m, 2H),
7.68(d, 1H, J=13.25Hz), 7.85(t, 1H), 7.37(m, 2H)
Example 16 : N-(4-Cyano-7-benzimidazolyl)-N'-(2-bromophenyl) urea *H NMR
(Acetone-d 6 ) 8 11.81(ps, 1H), 9.45(s, 1H), 8.84(s, 1H), 8.34(s, 1H), 8.26(m, 2H),
20 7.65(d, 2H), 7.41(t, 1H), 7.06(t, 1H)
Example 17 : N-(5-cyano-benzimidazolin-3-thione)-N'-(2,3-dichlorophenyl) urea *H
NMR (DMSO-d 6 ) 8 11.54(s, 1H), 10.42(s, 1H), 9.52(s, 1H), 8.62(s, 1H), 8.15(m,
1H), 7.54(d, 1H, J=13.25Hz), 7.40-7.30(t, m, 3H)
25
Example 18 : N-(5-cyano-N-cyano-2-guanidine)-N'-(2-bromophenyl) urea NMR
(DMSO-c£ 6 ) & H-84(s, 1H), 11.02(s, 1H), 9.66(s, 1H), 8.42(s, 1H), 8.04(d,
1H, J=13.25Hz), 7.66(d, 1H, J=13.25Hz), 7.50(m, 1H), 7.40(t, 1H), 7.06(t,
1H)
30
Example 19 : N-(4-Cyano-2-oxo-3-methylbenzimidazol-7-yl)-N'-(2-bromophenyl)
urea, alternatively called: N-4-(7-Cyano-l-methylbenzimidazolin-2-one)-N'-(2-
bromophenyl) urea *H NMR (DMSO-</ 6 ) d 10.89(s, 1H), 9.39(s, 1H), 8.30(s, 1H),
8.10(d, 1H, J=13.25), 7.76(d, 1H, J=13.25Hz), 7.45-7.32(m, 2H), 7.26(d, 1H,
35 J=13.25), 7.03 (t, 1H), 3.57 (s, 3H).
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METHOD OF TREATMENT
The compounds of Formula (I) and/or Formula (II), or pharmaceutically
acceptable salts thereof, can be used in the manufacture of a medicament for the
prophylactic or therapeutic treatment of any disease state in a human, or other
5 mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine
production by such mammal's cell, such as but not limited to monocytes and/or
macrophages, or other chemokines which bind to the IL-8 a or b receptor, also
referred to as the type I or type II receptor.
For purposes herein, the term "compounds of Formula (I)", or "Formula (I)"
10 will also refer to "compounds of Formula (II)" or "Formula (II)" unless otherwise
indicated.
Accordingly, the present invention provides a method of treating a
chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a
or b receptor and which method comprises administering an effective amount of a
15 compound of Formula (I) or a pharmaceutically acceptable salt thereof. In
particular, the chemokines are IL-8, GROa, GROp, GROy, NAP-2, or ENA-78.
The compounds of Formula (I) are administered in an amount sufficient to
inhibit cytokine function, in particular IL-8, GROa, GROp, GROy, NAP-2, or
ENA-78, such that they are biologically regulated down to normal levels of
20 physiological function, or in some case to subnormal levels, so as to ameliorate the
disease state. Abnormal levels of IL-8, GROa, GROp, GROy, NAP-2, or ENA-78
for instance in the context of the present invention, constitute: (i) levels of free IL-8
greater than or equal to 1 picogram per mL; (ii) any cell associated IL-8, GROa,
GROb, GROg, NAP-2, or ENA-78 above normal physiological levels; or (iii) the
25 presence of IL-8, GROa, GROP, GROy, NAP-2, or ENA-78 above basal levels in
cells or tissues in which IL-8, GROa, GROp, GROy, NAP-2, or ENA-78
respectively, is produced.
There are many disease states in which excessive or unregulated IL-8
production is implicated in exacerbating and/or causing the disease. Chemokine
30 mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic
obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory
bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxic
shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion
injury, glomerulonephritis, thrombosis, graft vs. host reaction, Alzheimer's disease,
35 allograft rejections, malaria, restinosis, angiogenesis or undesired hematopoietic
stem cells release.
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These diseases are primarily characterized by massive neutrophil infiltration,
T-cell infiltration, or neovascular growth, and are associated with increased IL-8,
GROoc, GRO(3, GROy or NAP-2 production which is responsible for the chemotaxis
of neutrophils into the inflammatory site or the directional growth of endothelial
5 cells. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8,
GROoc, GROp, GROy or NAP-2 has the unique property of promoting neutrophil
chemotaxis, enzyme release including but not limited to elastase release as well as
superoxide production and activation. The a-chemokines but particularly GROoc,
GROp, GROy or NAP-2, working through the IL-8 type I or II receptor can promote
10 the neovascularization of tumors by promoting the directional growth of endothelial
cells. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead
to a direct reduction in the neutrophil infiltration.
Recent evidence also implicates the role of chemokines in the treatment of
HIV infections, Littleman et al., Nature 381, pp661 (1996) and Koup et al., Nature
15 381, pp 667 (1996).
The present invention also provides for a means of treating, in an acute setting, as
well as preventing, in those individuals deemed susceptible to, CNS injuries by the
chemokine receptor antagonist compounds of Formula (I).
CNS injuries as defined herein include both open or penetrating head trauma,
20 such as by surgery, or a closed head trauma injury, such as by an injury to the head
region. Also included within this definition is ischemic stroke, particularly to the
brain area.
Ischemic stroke may be defined as a focal neurologic disorder that results
from insufficient blood supply to a particular brain area, usually as a consequence of
25 an embolus, thrombi, or local atheromatous closure of the blood vessel. The role of
inflammatory cytokines in this are has been emerging and the present invention
provides a mean for the potential treatment of these injuries. Relatively little
treatment, for an acute injury such as these has been available.
TNF-oc is a cytokine with proinflammatory actions, including endothelial
30 leukocyte adhesion molecule expression. Leukocytes infiltrate into ischemic brain
lesions and hence compounds which inhibit or decrease levels of TNF would be
useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7,
pp 1481-88 (1994) whose disclosure is incorporated herein by reference.
Models of closed head injuries and treatment with mixed 5-LO/CO agents is
35 discussed in Shohami et al., J. of Vaisc & Clinical Physiology and Pharmacology,
Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure is incorporated herein by
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reference. Treatment which reduced edema formation was found to improve
functional outcome in those animals treated.
The compounds of Formula (I) are administered in an amount sufficient to
inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these
5 receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation.
The discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is
based upon the effects of the compounds of Formulas (I) in the in vitro receptor
binding assays which are described herein. The compounds of Formula (I) have
been shown to be inhibitors of type II IL-8 receptors.
10 As used herein, the term "IL-8 mediated disease or disease state" refers to
any and all disease states in which IL-8, GROa, GRO(3, GROy, NAP-2, or ENA-78
plays a role, either by production of IL-8, GROa, GROp\ GROy, NAP-2, or ENA-78
themselves, or by IL-8, GROa, GROp\ GROy, NAP-2, or ENA-78 causing another
monokine to be released, such as but not limited to IL-1, IL-6 or TNF. A disease
15 state in which, for instance, IL-1 is a major component, and whose production or
action, is exacerbated or secreted in response to IL-8, would therefore be considered
a disease stated mediated by IL-8.
As used herein, the term "chemokine mediated disease or disease state" refers
to any and all disease states in which a chemokine which binds to an IL-8 a or b
20 receptor plays a role, such as but not limited to IL-8, GROa, GRO|3, GROy, NAP-2,
or ENA-78. This would include a disease state in which, IL-8 plays a role, either by
production of IL-8 itself, or by IL-8 causing another monokine to be released, such
as but not limited to IL-1, IL-6 or TNF. A disease state in which, for instance, IL-1
is a major component, and whose production or action, is exacerbated or secreted in
25 response to IL-8, would therefore be considered a disease stated mediated by IL-8.
As used herein, the term "cytokine" refers to any secreted polypeptide that
affects the functions of cells and is a molecule which modulates interactions between
cells in the immune, inflammatory or hematopoietic response. A cytokine includes,
but is not limited to, monokines and lymphokines, regardless of which cells produce
30 them. For instance, a monokine is generally referred to as being produced and
secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other
cells however also produce monokines, such as natural killer cells, fibroblasts,
basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells,
epideral keratinocytes and B -lymphocytes. Lymphokines are generally referred to as
35 being produced by lymphocyte cells. Examples of cytokines include, but are not
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limited to, Interleukin- 1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor
Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF-B).
As used herein, the term "chemokine" refers to any secreted polypeptide that
affects the functions of cells and is a molecule which modulates interactions between
5 cells in the immune, inflammatory or hematopoietic response, similar to the term
"cytokine" above. A chemokine is primarily secreted through cell transmembranes
and causes chemotaxis and activation of specific white blood cells and leukocytes,
neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth
muscle cells. Examples of chemokines include, but are not limited to, IL-8, GROa,
10 GROp, GROy, NAP-2, ENA-78, IP- 10, MlP-la, MlP-b, PF4, and MCP 1, 2, and 3.
In order to use a compound of Formula (I) or a pharmaceutically acceptable
salt thereof in therapy, it will normally be formulated into a pharmaceutical
composition in accordance with standard pharmaceutical practice. This invention,
therefore, also relates to a pharmaceutical composition comprising an effective, non-
15 toxic amount of a compound of Formula (I) and a pharmaceutically acceptable
carrier or diluent.
Compounds of Formula (I), pharmaceutically acceptable salts thereof and
pharmaceutical compositions incorporating such may conveniently be administered
by any of the routes conventionally used for drug administration, for instance, orally,
20 topically, parenterally or by inhalation. The compounds of Formula (I) may be
administered in conventional dosage forms prepared by combining a compound of
Formula (I) with standard pharmaceutical carriers according to conventional
procedures. The compounds of Formula (I) may also be administered in
conventional dosages in combination with a known, second therapeutically active
25 compound. These procedures may involve mixing, granulating and compressing or
dissolving the ingredients as appropriate to the desired preparation. It will be
appreciated that the form and character of the pharmaceutically acceptable character
or diluent is dictated by the amount of active ingredient with which it is to be
combined, the route of administration and other well-known variables. The
30 carrier(s) must be "acceptable" in the sense of being compatible with the other
ingredients of the formulation and not deleterious to the recipient thereof.
The pharmaceutical carrier employed may be, for example, either a solid or
liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar,
pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid
35 carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or
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diluent may include time delay material well known to the art, such as glyceryl
mono-stearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid
carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in
5 powder or pellet form or in the form of a troche or lozenge. The amount of solid
carrier will vary widely but preferably will be from about 25mg. to about lg. When
a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft
gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid
suspension.
10 Compounds of Formula (I) may be administered topically, that is by non-
systemic administration. This includes the application of a compound of Formula (I)
externally to the epidermis or the buccal cavity and the instillation of such a
compound into the ear, eye and nose, such that the compound does not significantly
enter the blood stream. In contrast, systemic administration refers to oral,
15 intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid
preparations suitable for penetration through the skin to the site of inflammation
such as liniments, lotions, creams, ointments or pastes, and drops suitable for
administration to the eye, ear or nose. The active ingredient may comprise, for
20 topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by
weight of the formulation. It may however comprise as much as 10% w/w but
preferably will comprise less than 5% w/w, more preferably from 0. 1% to 1% w/w
of the formulation.
Lotions according to the present invention include those suitable for
25 application to the skin or eye. An eye lotion may comprise a sterile aqueous solution
optionally containing a bactericide and may be prepared by methods similar to those
for the preparation of drops. Lotions or liniments for application to the skin may
also include an agent to hasten drying and to cool the skin, such as an alcohol or
acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis
30 oil.
Creams, ointments or pastes according to the present invention are semi-solid
formulations of the active ingredient for external application. They may be made by
mixing the active ingredient in finely-divided or powdered form, alone or in solution
or suspension in an aqueous or non-aqueous fluid, with the aid of suitable
35 machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons
such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage;
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an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or
its derivatives or a fatty acid such as steric or oleic acid together with an alcohol
such as propylene glycol or a macrogel. The formulation may incorporate any
suitable surface active agent such as an anionic, cationic or non-ionic surfactant such
5 as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such
as natural gums, cellulose derivatives or inorganic materials such as silicaceous
silicas, and other ingredients such as lanolin, may also be included.
Drops according to the present invention may comprise sterile aqueous or
oily solutions or suspensions and may be prepared by dissolving the active
10 ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent
and/or any other suitable preservative, and preferably including a surface active
agent. The resulting solution may then be clarified by filtration, transferred to a
suitable container which is then sealed and sterilized by autoclaving or maintaining
at 98-100 °C. for half an hour. Alternatively, the solution may be sterilized by
15 filtration and transferred to the container by an aseptic technique. Examples of
bactericidal and fungicidal agents suitable for inclusion in the drops are
phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and
chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily
solution include glycerol, diluted alcohol and propylene glycol.
20 Compounds of formula (I) may be administered parenterally, that is by
intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or
intraperitoneal administration. The subcutaneous and intramuscular forms of
parenteral administration are generally preferred. Appropriate dosage forms for such
administration may be prepared by conventional techniques. Compounds of
25 Formula (I) may also be administered by inhalation, that is by intranasal and oral
inhalation administration. Appropriate dosage forms for such administration, such
as an aerosol formulation or a metered dose inhaler, may be prepared by
conventional techniques.
For all methods of use disclosed herein for the compounds of Formula (I),
30 the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg
of total body weight. The daily parenteral dosage regimen about 0.001 to about 80
mg/kg of total body weight. The daily topical dosage regimen will preferably be
from 0. 1 mg to 150 mg, administered one to four, preferably two or three times
daily. The daily inhalation dosage regimen will preferably be from about 0.01
35 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art
that the optimal quantity and spacing of individual dosages of a compound of
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Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the
nature and extent of the condition being treated, the form, route and site of
administration, and the particular patient being treated, and that such optimums can
be determined by conventional techniques. It will also be appreciated by one of skill
5 in the art that the optimal course of treatment, i.e., the number of doses of a
compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day
for a defined number of days, can be ascertained by those skilled in the art using
conventional course of treatment determination tests.
The invention will now be described by reference to the following biological
10 examples which are merely illustrative and are not to be construed as a limitation of
the scope of the present invention.
BIOLOGICAL EXAMPLES
The IL-8, and Gro-a chemokine inhibitory effects of compounds of the
15 present invention are determined by the following in vitro assay:
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Receptor Binding Assays:
il-8 (human recombinant) is obtained from Amersham Corp.,
Arlington Heights, IL, with specific activity 2000 Ci/mmol. Gro-a is obtained from
NEN- New England Nuclear. All other chemicals are of analytical grade. High
5 levels of recombinant human IL-8 type a and b receptors were individually
expressed in Chinese hamster ovary cells as described previously (Holmes, et al.,
Science, 1991, 253, 1278). The Chinese hamster ovary membranes were
homogenized according to a previously described protocol (Haour, et al., J Biol
Chem., 249 pp 2195-2205 (1974)). Except that the homogenization buffer is
10 changed to lOmM Tris-HCL, ImM MgS04, 0.5mM EDTA (ethylene-diaminetetra-
acetic acid), lm MPMSF (a-toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH 7.5.
Membrane protein concentration is determined using Pierce Co. micro-assay kit
using bovine serum albumin as a standard. All assays are performed in a 96-well
micro plate format. Each reaction mixture contains 125 I IL-8 (0.25 nM) or 125 I
15 Gro-a and 0.5 ug/mL of IL-8Ra or 1 .0 ug/mL of IL-8Rb membranes in 20 mM Bis-
Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0, containing 1.2 mM MgS04, 0.1
mM EDTA, 25 mM NaCl and 0.03% CHAPS. In addition, drug or compound of
interest is added which has been pre-dissolved in DMSO so as to reach a final
concentration of between 0.0 InM and 100 uM. The assay is initiated by addition of
20 125i_IL_8. After 1 hour at room temperature the plate is harvested using a Tomtec
96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/
0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1 mM MgS04,
0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter is then dried and counted on the
Betaplate liquid scintillation counter. The recombinant IL-8 Ra, or Type I, receptor
25 is also referred to herein as the non-permissive receptor and the recombinant IL-8
Rb, or Type II, receptor is referred to as the permissive receptor.
Representative compounds of Formula (I), and (II), Examples 1 to 1 1, and 13
to 19 herein demonstrated positive inhibitory activity of < 30 umg in this assay. For
The compound of Example 12 did not demonstrate activity at <30 umg in this assay,
30 likely due to solubility issues.
Chemotaxis Assay :
The in vitro inhibitory properties of these compounds are determined in the
neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol.
35 I, Suppl 1, Unit 6.12.3., whose disclosure is incorporated herein by reference in its
entirety. Neutrophils where isolated from human blood as described in Current
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Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1, whose disclosure is
incorporated herein by reference in its entirety. The chemoattractants IL-8, GRO-a,
GRO-b, GRO-g and NAP-2 are placed in the bottom chamber of a 48 multiwell
chamber (Neuro Probe, Cabin John, MD) at a concentration between 0.1 and 100
5 nM. The two chambers are separated by a 5um polycarbonate filter. When
compounds of this invention are tested, they are mixed with the cells (0.001 - 1000
nM) just prior to the addition of the cells to the upper chamber. Incubation is
allowed to proceed for between about 45 and 90 min. at about 37°C in a humidified
incubator with 5% CO2. At the end of the incubation period, the polycarbonate
10 membrane is removed and the top side washed, the membrane then stained using the
Diff Quick staining protocol (Baxter Products, McGaw Park, IL, USA). Cells which
have chemotaxed to the chemokine are visually counted using a microscope.
Generally, four fields are counted for each sample, these numbers are averaged to
give the average number of cells which had migrated. Each sample is tested in
15 triplicate and each compound repeated at least four times. To certain cells (positive
control cells) no compound is added, these cells represent the maximum chemotactic
response of the cells. In the case where a negative control (unstimulated) is desired,
no chemokine is added to the bottom chamber. The difference between the positive
control and the negative control represents the chemotactic activity of the cells.
20
Elastase Release Assay:
The compounds of this invention are tested for their ability to prevent
Elastase release from human neutrophils. Neutrophils are isolated from human
blood as described in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1.
25 PMNs 0.88 x 10 6 cells suspended in Ringer's Solution (NaCl 118, KC1 4.56,
NaHC03 25, KH2P04 1.03, Glucose 11.1, HEPES 5 mM, pH 7.4) are placed in
each well of a 96 well plate in a volume of 50 ul. To this plate is added the test
compound (0.001 - 1000 nM) in a volume of 50 ul, Cytochalasin B in a volume of
50 ul (20ug/ml) and Ringers buffer in a volume of 50 ul. These cells are allowed to
30 warm (37 °C, 5% C02, 95% RH) for 5 min before IL-8, GROa, GROb, GROg or
NAP-2 at a final concentration of 0.01 - 1000 nM was added. The reaction is
allowed to proceed for 45 min. before the 96 well plate is centrifuged (800 xg 5
min.) and 100 ul of the supernatant removed. This supernatant is added to a second
96 well plate followed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-
35 AMC, Nova Biochem, La Jolla, CA) to a final concentration of 6 ug/ml dissolved in
phosphate buffered saline. Immediately, the plate is placed in a fluorescent 96 well
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plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min.
intervals according to the method of Nakajima et al J. Biol Chem 254 4027 (1979).
The amount of Elastase released from the PMNs is calculated by measuring the rate
of MeOSuc- Ala- Ala-Pro- Val-AMC degradation.
5
TNF-a in Traumatic Brain Injury Assay
The present assay provides for examination of the expression of tumor necrosis
factor mRNA in specific brain regions which follow experimentally induced lateral fluid-
percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n=42) were
10 anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and subjected to lateral fluid-
percussion brain injury of moderate severity (2.4 atm.) centered over the left
temporaparietal cortex (n=18), or "sham" treatment (anesthesia and surgery without injury,
n=18). Animals are sacrificed by decapitation at 1, 6 and 24 hr. post injury, brains
removed, and tissue samples of left (injured) parietal cortex (LC), corresponding area in the
15 contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA),
corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and right
hippocampus (RH) are prepared. Total RNA was isolated and Northern blot hybridization
is performed and quantitated relative to an TNF-a positive control RNA (macrophage =
100%). A marked increase of TNF- a mRNA expression is observed in LH (104±17% of
20 positive control, p < 0.05 compared with sham), LC (105±21%, p< 0.05) and LA (69±8%,
p < 0.01) in the traumatized hemisphere 1 hr. following injury. An increased TNF- a
mRNA expression is also observed in LH (46±8%, p < 0.05), LC (30±3%, p < 0.01) and
LA (32±3%, p < 0.01) at 6 hr. which resolves by 24 hr. following injury. In the
contralateral hemisphere, expression of TNF- a mRNA is increased in RH (46±2%, p <
25 0.01), RC (4±3%) and RA (22±8%) at 1 hr. and in RH (28±1 1%), RC (7±5%) and RA
(26±6%, p < 0.05) at 6 hr. but not at 24 hr. following injury. In sham (surgery without
injury) or naive animals, no consistent changes in expression of TNF- a mRNA are
observed in any of the 6 brain areas in either hemisphere at any times. These results
indicate that following parasagittal fluid-percussion brain injury, the temporal expression
30 of TNF-a mRNA is altered in specific brain regions, including those of the non-traumatized
hemisphere. Since TNF- a is able to induce nerve growth factor (NGF) and stimulate the
release of other cytokines from activated astrocytes, this post-traumatic alteration in gene
expression of TNF-a plays an important role in both the acute and regenerative response to
CNS trauma.
35
CNS Injury model for IL-b mRNA
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This assay characterizes the regional expression of interleukin- 1 B (IL-1B)
mRNA in specific brain regions following experimental lateral fluid-percussion
traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n=42) are
anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and subjected to lateral
5 fluid-percussion brain injury of moderate severity (2.4 atm.) centered over the left
temporaparietal cortex (n=18), or "sham" treatment (anesthesia and surgery without
injury). Animals are sacrificed at 1, 6 and 24 hr. post injury, brains removed, and
tissue samples of left (injured) parietal cortex (LC), corresponding area in the
contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA),
10 corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and
right hippocampus (RH) are prepared. Total RNA is isolated and Northern blot
hybridization was performed and the quantity of brain tissue IL-1B mRNA is
presented as percent relative radioactivity of IL-1B positive macrophage RNA which
was loaded on same gel. At 1 hr. following brain injury, a marked and significant
15 increase in expression of IL-1B mRNA is observed in LC (20.0±0.7% of positive
control, h=6, p < 0.05 compared with sham animal), LH (24.5±0.9%, p < 0.05) and
LA (21.5±3.1%, p < 0.05) in the injured hemisphere, which remained elevated up to
6 hr. post injury in the LC (4.0+0.4%, n=6, p < 0.05) and LH (5.0±1.3%, p < 0.05).
In sham or naive animals, no expression of IL-1B mRNA is observed in any of the
20 respective brain areas. These results indicate that following TBI, the temporal
expression of IL-1B mRNA is regionally stimulated in specific brain regions. These
regional changes in cytokines, such as IL-1B play a role in the post- traumatic.
All publications, including but not limited to patents and patent applications,
cited in this specification are herein incorporated by reference as if each individual
25 publication were specifically and individually indicated to be incorporated by reference
herein as though fully set forth.
The above description fully discloses the invention including preferred
embodiments thereof. Modifications and improvements of the embodiments
30 specifically disclosed herein are within the scope of the following claims. Without
further elaboration, it is believed that one skilled in the are can, using the preceding
description, utilize the present invention to its fullest extent. Therefore the
Examples herein are to be construed as merely illustrative and not a limitation of the
scope of the present invention in any way. The embodiments of the invention in
35 which an exclusive property or privilege is claimed are defined as follows.
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What is Claimed Is:
1 . A compound of the formula:
wherein
R is -NH -C(X 2 )-NH- (CRi3Ri4) v - Z;
I \
(CR 15 R 16 )p
ZisW, HET, ( y ) n , an optionally substituted Cj. 10 alkyl, an
optionally substituted C2-10 alkenyl, or an optionally substituted C2-I0 alkynyl;
10 X is C(Xi) 2 , C(O), C(S), S(0) 2 , PO(OR 4 ), or C=N-R 19 ;
Xi is independently hydrogen, halogen, Ci-io alkyl, NR4R5, Ci-io alkyl-NR4R5,
C(0)NR4R5, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted
Ci-io alkoxy, hydroxy, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci_ 4 alkyloxy,
heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci- 4 alkyl, or heteroaryl
15 Ci-4 alkyloxy;
X2 is =0, or =S;
Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted
Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io
alkoxy; azide; (CR 8 R 8 )q S(0) t R4, hydroxy; hydroxy Ci-4alkyl; aryl; aryl C1.4
20 alkyl; aryloxy; aryl Ci- 4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic;
heterocyclic Ci- 4 alkyl; heteroaryl Ci_4 alkyloxy; aryl C2-10 alkenyl; heteroaryl
C 2 -10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )qNR4R5; C2-10 alkenyl
C(0)NR 4 R5; (CR 8 R8)q C(0)NR4R5; (CR 8 R 8 )q C(O)NR 4 Ri0; S(0)3R8;
(CR 8 R 8 )q C(0)Ri 1; C2-IO alkenyl C(0)Ri l; C2-10 alkenyl C(0)ORi 1;
25 C(0)Rn; (CR 8 R 8 )q C(0)ORi2; (CR 8 R 8 )q OC(O) Rn;
(CR 8 R 8 )qC(NR4)NR 4 R5; (CR 8 R 8 )q NR4C(NR 5 )Rn; (CR 8 R 8 )q
NR4C(0)Rn; (CR 8 R 8 )q NHS(0) 2 Rl7; (CR 8 R 8 )q S(0) 2 NR 4 R 5 ; or two R1
moieties together may form 0-(CH 2 ) s O or a 5 to 6 membered saturated or
unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing
30 moieties may all be optionally substituted;
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n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3 ;
q is 0, or an integer having a value of 1 to 10;
s is an integer having a value of 1 to 3;
5 t is 0, or an integer having a value of 1 or 2;
v is 0, or an integer having a value of 1 to 4;
p is an integer having a value of 1 to 3;
HET is an optionally substituted heteroaryl;
R.4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally
10 substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or
heterocyclic Ci_4 alkyl, or R4 and R5 together with the nitrogen to which they
are attached form a 5 to 7 member ring which may optionally comprise an
additional heteroatom selected from O/N/S;
15 Y is independently selected from hydrogen; halogen; nitro; cyano; halo substituted
Ci-io alkyl; Ci-10 alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci_io
alkoxy; azide; (CR 8 R 8 )q S(0) t R4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Ci-4
alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C1.4
alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl
20 C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )q NR4R5; C2-10 alkenyl
C(0)NR 4 R5; (CR 8 R 8 )q C(0)NR4R5; (CR 8 R 8 )q C(O)NR4Rl0; S(0) 3 R8;
(CR 8 R8)q C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)ORn;
(CR 8 R 8 )q C(0)ORi 2 ; (CR 8 R 8 )q OC(O) Rn; (CR 8 Rs)q NR4C(0)Rn;
(CR 8 R 8 )qC(NR4)NR 4 R5; (CR 8 R 8 )q NR 4 C(NR 5 )R n ; (CR 8 R8)q NHS(0) 2 R a ;
25 (CR 8 R 8 )q S(0)2NR4R5; or two Y moieties together may form 0-(CH2) s O or a
5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl,
and heterocyclic containing moieties may all be optionally substituted;
R6 and R7 are independently hydrogen or a Ci_4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
30 may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;
R8 is independently hydrogen or Ci_4 alkyl;
RlO is C 1-10 alkyl C(0)2R 8 ;
R\ 1 is hydrogen, Ci_4 alkyl, optionally substituted aryl, optionally substituted aryl
35 Ci-4alkyl, optionally substituted heteroaryl, optionally substituted
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heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC i_4alkyl;
Rl2 is hydrogen, Ci_io alkyl, optionally substituted aryl or optionally substituted
arylalkyl;
5 R13 and R14 are independently hydrogen, optionally substituted Ci_4 alkyl, or one
of R13 and R14 may be optionally substituted aryl;
R1 5 and R16 are independently hydrogen, or an optionally substituted Cj-4 alkyl;
Rl7 is Cl-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi_4alkyl, heterocyclic, or
heterocyclicCi_4alkyl, wherein the aryl, heteroaryl and heterocyclic moieties
10 may all be optionally substituted;
R1 g is hydrogen, optionally substituted Ci-io alkyl, Ci_io alkoxy, halosubstituted
Ci-io alkoxy, hydroxy, arylCi .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
Ci_4alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC \ .4 alkyl,
wherein all the aryl, heteroaryl and heterocyclic containing moieites may all be
15 optionally substituted;
Rl9 is cyano, nitro, S(0)2NR4R5, S(0)2Rn, alkyl, arylCi_4 alkyl, arylC 2-4
alkenyl, heteroaryl, heteroaryl-Ci_4alkyl, heteroarylC2-4 alkenyl, heterocyclic,
or heterocyclicC 1 _4 alkyl, wherein the alkyl, aryl, heteroaryl and heterocyclic
containing moieites may all be optionally substituted;
20 R a is NR6R7, alkyl, arylC]_4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
Ci_4alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC 1 .4 alkyl,
wherein the aryl, heteroaryl and heterocyclic containing moieites may all be
optionally substituted;
Wis
25 the E containing ring is optionally selected from
the asterix * denoting point of attachment of the ring;
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or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 wherein Ri is halogen, cyano, nitro,
CF3, C(0)NR4R5, alkenyl C(0)NR4R5, C(O) R4R1O, alkenyl C(0)ORi2,
5 heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or S(0)NR4R5.
3. The compound according to Claim 1 wherein X is C(O) or C(S).
4. The compound according to any of Claims 1 to 3 wherein Z is W.
10
5. The compound according to Claim 4 wherein Y is halogen, Ci_4 alkoxy,
optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy,
NR4R5, thioCi-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted
Ci-4alkyl, or hydroxy alkyl.
15
6. The compound according to Claim 1 which is:
N-4-(Benzimidazoline-2-one-N'-(2'-bromophenyl)urea;
N-4-( 1H.3H-2, 1 ,3-benzothiazole 2,2-dioxide)-N'-(2-bromophenyl) urea;
N-4-(7-Cyano- 1 -N-methyl-benzimidazoline-2-thione)-N'-(2,3-dichlorophenyl) urea;
20 N-4-(7-Cyano-benzimidazoline-2-thione)-N'-(2 bromophenyl) urea;
N-4-(7-Cyano- 1 -methyl-benzimidazoline-2-thione)-N'-(2 bromophenyl) urea;
N-(4-Cyano-2-oxo-3-methylbenzimidazol-7-yl)-N'-(2-bromophenyl) urea
N-4-(7-Cyano-benzimidazoline-2-one)-N'-(2-bromophenyl)urea;
N-4-(7-Cyano-benzimidazoline-2-thione)-N'-(2,3-dichlorophenyl) urea;
25 N-4-(7-Cyano benzimidazoline-2-imine)-N'-(2-bromophenyl) urea; or
a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising an effective amount of a
compound according to Claim 1, and a pharmaceutically acceptable carrier or
30 diluent.
8. A method of treating a chemokine mediated disease in a mammal in need
thereof, wherein the chemokine binds to an IL-8 a or b receptor, which method
comprises administering to said mammal an effective amount of a compound
35 according to Claim 1 .
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9. The method according to Claim 8 wherein the mammal is afflicted with a
chemokine mediated disease selected from psoriasis, atopic dermatitis, asthma,
chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis,
inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock,
5 endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and
renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft
vs. host reaction, or allograft rejections.
10. A compound of the formula:
10
(Fti)m
wherein
R is -NH -C(X 2 )-NH- (CRi 3 Ri4) v - Z;
I \
^(CR 15 R 16 )p
15 Z is W, HET, , optionally substituted Ci _io alkyl, optionally
substituted C2-IO alkenyl, or optionally substituted C2-I0 alkynyl;
Xis N, or C(Xi);
X! is hydrogen, halogen, Ci_io alkyl, NR4R5, Ci-io alkyl-NR4R5, C(0)NR4R5,
optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy,
20 hydroxy, aryl, aryl C1-4 alkyl, aryloxy; aryl Ci-4 alkyloxy, heteroaryl,
heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, or heteroaryl C1-4
alkyloxy;
X2 is =0, or =S;
Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted
25 C1-10 alkyl; Ci-io alkyl; C2-10 alkenyl; Ci_io alkoxy; halosubstituted Ci_io
alkoxy; azide; (CRgRg)q S(0) t R4, hydroxy; hydroxy Ci_4alkyl; aryl; aryl Ci_4
alkyl; aryloxy; aryl Ci_4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic;
heterocyclic Ci_4alkyl; heteroaryl Ci-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl
C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CRgRg)qNR4R5 ; C2-10 alkenyl
30 C(0)NR 4 R5; (CR 8 Rg)q C(0)NR 4 R5; (CR 8 R8)q C(O)NR 4 Rl0; S(0) 3 R 8 ;
(CR 8 R 8 )q C(0)Rn; C2-10 alkenyl C(0)Rn; C 2 -10 alkenyl C(0)ORn;
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C(0)Rn; (CR 8 R 8 )q C(0)ORi 2 ; (CR 8 R 8 )q OC(O) Rn;
(CR 8 R 8 )qC(NR 4 )NR 4 R5; (CR 8 R 8 )q NR4C(NR 5 )Rn; (CR 8 R 8 )q
NR4C(0)Rn; (CR 8 R 8 )q NHS(0) 2 Ri7; or (CR 8 R 8 )q S(0) 2 NR 4 R 5 ; or two Ri
moieties together may form 0-(CH2)sO or a 5 to 6 membered saturated or
5 unsaturated ring; and wherein the aryl, heteroaryl and heterocylic containing
moieites may all be optionaly substituted;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
p is an integer having a value of 1 to 3;
10 q is 0, or an integer having a value of 1 to 10;
s is an integer having a value of 1 to 3;
t is 0, or an integer having a value of 1 or 2;
v is 0, or an integer having a value of 1 to 4;
HET is an optionally substituted heteroaryl;
15 R4 and R5 are independently hydrogen, optionally substituted C1-.4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci_4alkyl, heterocyclic, or
heterocyclic Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they
are attached form a 5 to 7 member ring which may optionally comprise an
20 additional heteroatom selected from O/N/S;
Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted
Ci-io alkyl; Ci-io alkyl; C 2 -10 alkenyl; Ci-io alkoxy; halosubstituted Ci_io
alkoxy; azide; (CR 8 R 8 )q S(0) t R4; hydroxy; hydroxyCi -4alkyl; aryl; aryl Ci-4
alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci_ 4
25 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C 2 -io alkenyl; heteroaryl
C2-10 alkenyl; heterocyclic C 2 -10 alkenyl; (CR 8 R 8 )q NR4R5; C2-10 alkenyl
C(0)NR4R5; (CR 8 R 8 )q C(0)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 Ri 0 ; S(0) 3 R 8 ;
(CR 8 R 8 )q C(0)Rn; C2-10 alkenyl C(0)Rn; C2-10 alkenyl C(0)ORn;
(CR 8 R 8 )q C(0)ORl 2 ; (CR 8 R 8 )q OC(O) Rn; (CR 8 R 8 )q NR 4 C(0)Rn;
30 (CR 8 R 8 )qC(NR4)NR4R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )Ri 1 ; (CR 8 R 8 )q NHS(0) 2 R a ;
or (CR 8 R 8 )q S(0>2NR4R5; or two Y moieties together may form 0-(CH2)sO or
a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl
and hetorocyclic containing moieities may all be optionally substituted;
R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
35 with the nitrogen to which they are attached form a 5 to 7 member ring which ring
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WO 98/32439
PCT/US98/01291
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;
R.8 is independently hydrogen or Ci -.4 alkyl;
RlOisCi-ioalkyl C(0) 2 R8;
5 Ri 1 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl
Ci_4alkyl, optionally substituted heteroaryl, optionally substituted
heteroarylCi_4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC 1 _4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
10 arylalkyl;
Rl3 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one
of R13 and R14 may be optionally substituted aryl;
R1 5 and Rig are independently hydrogen, or an optionally substituted Ci_4 alkyl;
Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or
15 heterocyclicC i_4alkyl, wherein the aryl, heteroaryl and heterocyclic moieites
may all be optionally substituted;
R a is NR6R7, alkyl, arylCi.4 alkyl, arylC2_4 alkenyl, heteroaryl, heteroaryl-
Ci_4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC \ .4 alkyl,
wherein the aryl, heteroaryl and heterocyclic moieties may all be optionally
20 substituted;
Wis
the E containing ring is optionally selected from
the asterix * denoting point of attachment of the ring;
25 or a pharmaceutical^ acceptable salt thereof.
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WO 98/32439
PCT/US98/01291
1 1. The compound according to Claim 10 wherein Ri is halogen, cyano, nitro,
CF3, C(0)NR4R5, alkenyl C(0)NR4R5, C(O) R4R1O, alkenyl C(0)ORi2,
heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(0)NR4R5.
5 12. The compound according to Claim 10 wherein X is N.
13. The compound according to any of Claims 10 to 12 wherein Z is W.
14. The compound according to Claim 13 wherein Y is halogen, C1-.4 alkoxy,
10 optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy,
NR4R5, thioCi-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted
Ci_4alkyl, or hydroxy alkyl.
15. The compound according to Claim 10 which is:
15 N-7-(Benzotriazole)-N'-(2-bromophenyl)urea;
N-7-(4-Bromobenzotriazole)-N'-(2,3-dichorophenyl)urea;
N-7-(4-Bromo-2-trifluoromethyl-benzimidazolyl)-N'-(2-bromophenyl)urea;
N-4-(2-Trifluoromethyl-benzimidazolyl)-N'-(2-bromophenyl)urea;
N-7-(4-Cyano-benzotriazole)-N'-(2,3-dichlorophenyl) urea;
20 N-(2-Bromophenyl)-N'-7-(4-cyano-benzotriazole) urea;
N-7-(4-Cyano-2-trifluoromethyl-benzimidazolyl)-N'-(2-bromophenyl) urea;
N-7-(4-Cyano-benzimidazolyl)-N'-(2,3-dichlorophenyl) urea;
N-7-(4-Cyano-benzimidazolyl)-N'-(2-bromophenyl) urea;
N-7-(4-Cyano-benzotriazole)-N'-(2,3-dichorophenyl)urea;
25 or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising an effective amount of a
compound according to Claim 10, and a pharmaceutically acceptable carrier or
diluent.
30
17. A method of treating a chemokine mediated disease in a mammal in need
thereof, wherein the chemokine binds to an IL-8 a or b receptor, which method
comprises administering to said mammal an effective amount of a compound
according to Claim 10.
35
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WO 98/32439
PCT/US98/01291
18. The method according to Claim 17 wherein the mammal is afflicted with a
chemokine mediated disease selected from psoriasis, atopic dermatitis, asthma,
chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis,
inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock,
5 endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and
renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft
vs. host reaction, or allograft rejections.
19. A process for making a compound of the formula:
10
N
by reacting a compound of the formula:
with sodium nitrite in a protic solvent, followed by reduction of the nitro group to
15 yield a compound of Formula (III).
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20. A process for making a compound of Formula (IV)
which process comprises reacting 2-cyano-5-nitroaniline with tetramethyl hydrazine
iodide, a strong hindered base, and an aprotic solvent to yield a compound of
5 Formula (IV).
-51 -
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/01291
A. CLASSIFICATION OF SUBJECT MATTER
IPC(6) :Pleasc See Extra Sheet.
US CL :Please See Extra Sheet.
According to International Patent Classification (IPC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
U.S. : 514/111, 243, 362, 394, 395; 544/183; 548/135, 304.4, 306.4; 558/80
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
STN/CAS, structure search
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
Chem. abstr., Vol. 123, No. 3, 17 July 1995 (Columbus, OH, USA),
page 849, column 2, abstract 33047g, SATO et al., 'Preparation of
l-(imidazolylalkyl)-3-ureido-l,4-benzodiazepine derivatives as
cholecystokinin (CCK) antagonists.' JP 0702843, 06 January 1995.
1-20
Chem. abstr., Vol. 82,
page 428, column 1,
No. 7, 17 February 1975 (Columbus, OH)
abstract 43273b, PILGRAM, K., '4,7-
Disubstituted 2,1,3-benzothiadiazoles. ' J. Heterocycl. Chem., 1974,
11(5), 835-837.
1-20
Further documents are listed in the continuation of Box C. | j See patent family annex.
"L"
"O"
"P"
Special categories of cited documents: "T"
document defining the general state of the art which is not considered
to be of particular relevance
"X"
earlier document published on or after the international filing date
document which may throw doubts on priority claim(s) or which is
cited to establish the publication date of another citation or other
special reason (as specified) "Y"
document referring to an oral disclosure, use, exhibition or other
means
document published prior to the international filing date but later than
later document published after the international filing date or priority
date and not in conflict with the application but cited to understand
the principle or theory underlying the invention
document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive step
when the document is taken alone
document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, such combination
being obvious to a person skilled in the art
document member of the same patent family
Date of the actual completion of the international search
09 APRIL 1998
Date of mailing of the international search report
1 8 WAY 1998
Name and mailing address of the ISA/US
Commissioner of Patents and Trademarks
Box PCT
Washington, D.C 20231
Facsimile No. (703) 305-3230
Authorized officer
RICHARD L. RAYMOND «^lM\J^_
Telephone No. (703) 308-1235 ^
M
Form PCT/ISA/210 (second sheefX-July 1992)*
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/01291
C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
A
Chem. abstr., Vol. 52, No. 22, 25 November 1958 (Columbus, OH)
columns 20185-20186, SEKIKAWA, I., 'Antitubercular
compounds. XIII. Preparation of some derivatives of benzimidazole
and 2,1,3-benzothiadiazoles.' Bull. Chem. Soc. Japan, 1958, 31,
252-254.
1-20
Form PCT/ISA/210 (continuation of second sheetX-July 1992)*
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/01291
A. CLASSIFICATION OF SUBJECT MATTER:
IPC (6):
A61K 31/41, 31/415, 31/53, 31/675; C07D 235/08, 235/26, 253/06, 285/14; C07F 9/6584
A. CLASSIFICATION OF SUBJECT MATTER:
US CL :
514/111, 243, 362, 394, 395; 544/183; 548/135, 304.4, 306.4; 558/80
Form PCT/ISA/210 (extra sheetXJuly 1992)*
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